BioPAX pathway converted from "Signaling by ROBO receptors" in the Reactome database.

Signaling by ROBO receptors

The Roundabout (ROBO) family encodes transmembrane receptors that regulate axonal guidance and cell migration. The major function of the Robo receptors is to mediate repulsion of the navigating growth cones. There are four human Robo homologues, ROBO1, ROBO2, ROBO3 and ROBO4. Most of the ROBOs have the similar ectodomain architecture as the cell adhesion molecules, with five Ig domains followed by three FN3 repeats, except for ROBO4. ROBO4 has two Ig and two FN3 repeats. The cytoplasmic domains of ROBO receptors are in general poorly conserved. However, there are four short conserved cytoplasmic sequence motifs, named CC0-3, that serve as binding sites for adaptor proteins. The ligands for the human ROBO1 and ROBO2 receptors are the three SLIT proteins SLIT1, SLIT2, and SLIT3; all of the SLIT proteins contain a tandem of four LRR (leucine rich repeat) domains at the N-terminus, termed D1-D4, followed by six EGF (epidermal growth factor)-like domains, a laminin G like domain (ALPS), three EGF-like domains, and a C-terminal cysteine knot domain. Most SLIT proteins are cleaved within the EGF-like region by unknown proteases (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). NELL2 is a ligand for ROBO3 (Jaworski et al. 2015). SLIT protein binding modulates ROBO interactions with the cytosolic adaptors. The cytoplasmic domain of ROBO1 and ROBO2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms it has been inferred that ROBO induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (ABL) and Enabled (Ena), or RAC1 activity (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). While there is some redundancy in the function of ROBO receptors, ROBO1 is implicated as the predominant receptor for axon guidance in ventral tracts, and ROBO2 is the predominant receptor for axon guidance in dorsal tracts. ROBO2 also repels neuron cell bodies from the floor plate (Kim et al. 2011).In addition to regulating axon guidance, ROBO1 and ROBO2 receptors are also implicated in regulation of proliferation and transition of primary to intermediate neuronal progenitors through a poorly characterized cross-talk with NOTCH-mediated activation of HES1 transcription (Borrell et al. 2012).Thalamocortical axon extension is regulated by neuronal activity-dependent transcriptional regulation of ROBO1 transcription. Lower neuronal activity correlates with increased ROBO1 transcription, possibly mediated by the NFKB complex (Mire et al. 2012).It is suggested that the homeodomain transcription factor NKX2.9 stimulates transcription of ROBO2, which is involved in regulation of motor axon exit from the vertebrate spinal code (Bravo-Ambrosio et al. 2012).Of the four ROBO proteins, ROBO4 is not involved in neuronal system development but is, instead, involved in angiogenesis. The interaction of ROBO4 with SLIT3 is involved in proliferation, motility and chemotaxis of endothelial cells, and accelerates formation of blood vessels (Zhang et al. 2009).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23Edited: Orlic-Milacic, Marija, 2017-08-04

Regulation of expression of SLITs and ROBOs

Expression of SLIT and ROBO proteins is regulated at the level of transcription, translation and protein localization and stability. LIM-homeodomain transcription factors LHX2, LHX3, LHX4, LHX9 and ISL1 have so far been implicated in a cell type-dependent transcriptional regulation of ROBO1, ROBO2, ROBO3 and SLIT2 (Wilson et al. 2008, Marcos-Mondejar et al. 2012, Kim et al. 2016). Homeobox transcription factor HOXA2 is involved in transcriptional regulation of ROBO2 (Geisen et al. 2008). Transcription of SLIT1 during optic tract development in Xenopus is stimulated by FGF signaling and may also involve the transcription factor HOXA2, but the mechanism has not been established (Atkinson-Leadbeater et al. 2010). PAX6 and the homeodomain transcription factor NKX2.2 are also implicated in regulation of SLIT1 transcription (Genethliou et al. 2009). An RNA binding protein, MSI1, binds ROBO3 mRNA and promotes its translation, thus increasing ROBO3 protein levels (Kuwako et al. 2010). A poorly studied E3 ubiquitin ligase ZSWIM8 promotes degradation of ROBO3 (Wang et al. 2013). ROBO1 is protein half-life is increased via deubiquitination of ROBO1 by a ubiquitin protease USP33 (Yuasa-Kawada et al. 2009, Huang et al. 2015). Interaction of SLIT2 with DAG1 (dystroglycan) is important for proper localization of SLIT2 at the floor plate (Wright et al. 2012). Interaction of SLIT1 with a type IV collagen COL4A5 is important for localization of SLIT1 to the basement membrane of the optical tectum (Xiao et al. 2011).

Authored: Orlic-Milacic, Marija, 2017-06-27Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

ISL1 binds the SLIT2 gene enhancer

Based on studies in mice, the transcription factor ISL1, in complex with either LHX3 or LHX4, binds to an evolutionarily conserved LIM-HD binding site in the enhancer of the SLIT2 gene, located in the sixth intron of the SLIT2 gene. The complex of ISL1 and LHX4 regulates SLIT2 expression in branchiomotor neurons, while the complex of ISL1 and LHX3 regulates SLIT2 expression in somatic motor neurons (Kim et al. 2016). From the previous structural studies of the ISL1 complex with LHX3, conducted using mouse and rat proteins, it is known that LDB1 is also part of this complex (Thaler et al. 2002).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Converted from EntitySet in Reactome

Reactome DB_ID: 9010608

nucleoplasmGO0005654

ISL1:LHX3/4:LDB1 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactomehttp://www.reactome.org

Reactome DB_ID: 9010561

ENSEMBL:ENSG00000145147 SLIT2SLIL3SLIT2

Homo sapiens

NCBI Taxonomy9606ENSEMBLENSG00000145147

Reactome DB_ID: 9010606

ISL1:LHX3/4:LDB1:SLIT2 gene [nucleoplasm]

ISL1:LHX3/4:LDB1:SLIT2 gene

Converted from EntitySet in Reactome

Reactome DB_ID: 9010608

Reactome DB_ID: 9010561

Reactome Database ID Release 759010606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010606ReactomeR-HSA-9010606

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010606.1Reactome Database ID Release 759010541Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010541ReactomeR-HSA-9010541

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010541.112150931Pubmed2002LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactionsThaler, Joshua PLee, Soo-KyungJurata, Linda WGill, GNPfaff, Samuel LCell 110:237-4927819291Pubmed2016ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neuronsKim, Kyung-TaiKim, NamheeKim, Hwan-KiLee, HojaeGruner, Hannah NGergics, PeterPark, ChungooMastick, Grant SPark, Hae-ChulSong, Mi-RyoungSci Rep 6:36491

SLIT2 gene expression is stimulated by ISL1

Based on studies in mice, the transcription factor ISL1, in complex with either LHX3 or LHX4, directly stimulates transcription of the SLIT2 gene. ISL1-mediated regulation of SLIT2 gene transcription in branchiomotor (BM) neurons and somatic motor (SM) neurons involves LHX4 and LHX3, respectively (Kim et al. 2016). Slit2 expression is diminished in Isl1 mutant mice (Lee et al. 2015).SLIT2 is one of gene suggested to be repressed by the transcription factor ARX, involved in neuronal proliferation, migration, maturation and differentiation, as well as axon guidance (reviewed by Friocourt and Parnavelas, 2011).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9010561

Reactome DB_ID: 375997

extracellular regionGO0005576

UniProt:O94813 SLIT2

SLIT2

SLIL3SLIT2FUNCTION Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal chord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal chord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration.SUBUNIT Interacts with GREM1 (By similarity). Homodimer. Binds ROBO1 and ROBO2 with high affinity.TISSUE SPECIFICITY Fetal lung and kidney, and adult spinal cord. Weak expression in adult adrenal gland, thyroid, trachea and other tissues examined.DOMAIN The leucine-rich repeat domain is sufficient for guiding both axon projection and neuronal migration, in vitro.

UniProtO94813

Chain Coordinates

EQUAL

1529

EQUAL

Reactome Database ID Release 759010539Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010539ReactomeR-HSA-9010539

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010539.322355284Pubmed2011Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiationFriocourt, GaëlleParnavelas, John GFront Cell Neurosci 5:2825843547Pubmed2015Slit and Semaphorin signaling governed by Islet transcription factors positions motor neuron somata within the neural tubeLee, HojaeKim, MinkyungKim, NamheeMacfarlan, ToddPfaff, Samuel LMastick, Grant SSong, Mi-RyoungExp. Neurol. 269:17-27

ACTIVATION

Reactome Database ID Release 759010614Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010614ReactomeR-HSA-9010614

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010614.1

Reactome DB_ID: 9010606

SLIT2 binds Dystroglycan

SLIT2 binds to dystroglycan (DAG1). The interaction involves the C-terminal region of human SLIT2. The species origin of the DAG1 construct was not specified and is assumed to be human. Dystroglycan is required for proper SLIT2 localization within the basement membrane and the floor plate. Dystroglycan glycosylation, mediated at least in part by B4GAT1 (B3GNT1) and ISPD, is likely required for its interaction with SLIT2, but it has not been annotated. Mice mutant for B4gat1, Ispd or Dag1 have axon guidance defects similar to those observed in Slit or Robo mutant mice (Wright et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 2328140

plasma membraneGO0005886Dystroglycan [plasma membrane]

Dystroglycan

Reactome DB_ID: 2328152

UniProt:Q14118 DAG1

DAG1

DAG1FUNCTION The dystroglycan complex is involved in a number of processes including laminin and basement membrane assembly, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, and epithelial polarization.SUBUNIT Monomer. Heterodimer of alpha- and beta-dystroglycan subunits which are the central components of the dystrophin-glycoprotein complex. This complex then can form a dystrophin-associated glycoprotein complex (DGC) which is composed of three subcomplexes: a cytoplasmic complex comprised of DMD (or UTRN), DTNA and a number of syntrophins, such as SNTB1, SNTB2, SNTG1 and SNTG2, the transmembrane dystroglycan complex, and the sarcoglycan-sarcospan complex. Interacts (via the N-terminal of alphaDAG1) with LARGE1; the interaction enhances laminin binding (By similarity). Interacts with SGCD. Interacts with AGR2 and AGR3. Interacts (betaDAG1) with DMD; the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (betaDAG1, via its PPXY motif) with UTRN (via its WWW and ZZ domains); the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (betaDAG1, via its phosphorylated PPXY motif) with the SH2 domain-containing proteins, FYN, CSK, NCK and SHC. Interacts (betaDAG1) with CAV3 (via a central WW-like domain); the interaction disrupts the binding of DMD. BetaDAG1 directly interacts with ANK3, but not with ANK2; this interaction does not interfere with DMD-binding and is required for retention at costameres (By similarity). Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Interacts with POMGNT1 (PubMed:27493216).SUBUNIT (Microbial infection) Interacts with lassa virus and lymphocytic choriomeningitis virus glycoprotein (PubMed:16254364, PubMed:19324387).SUBUNIT (Microbial infection) Interacts with surface molecules of mycobacterium leprae.TISSUE SPECIFICITY Expressed in a variety of fetal and adult tissues. In epidermal tissue, located to the basement membrane. Also expressed in keratinocytes and fibroblasts.PTM Autolytic cleavage produces the alpha and beta subunits. In cutaneous cells, as well as in certain pathological conditions, shedding of beta-dystroglycan can occur releasing a peptide of about 30 kDa.PTM SRC-mediated phosphorylation of the PPXY motif of the beta subunit recruits SH2 domain-containing proteins, but inhibits binding to WWW domain-containing proteins, DMD and UTRN. This phosphorylation also inhibits nuclear entry.

UniProtQ14118

EQUAL

653

EQUAL

Reactome DB_ID: 2328154

654

EQUAL

895

EQUAL

Reactome Database ID Release 752328140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2328140ReactomeR-HSA-2328140

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2328140.1

Reactome DB_ID: 9010869

SLIT2:Dystroglycan [plasma membrane]

SLIT2:Dystroglycan

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 2328140

Reactome Database ID Release 759010869Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010869ReactomeR-HSA-9010869

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010869.1Reactome Database ID Release 759010872Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010872ReactomeR-HSA-9010872

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010872.223217742Pubmed2012Dystroglycan organizes axon guidance cue localization and axonal pathfindingWright, Kevin MLyon, Krissy ALeung, HaiwenLeahy, Daniel JMa, LeGinty, David DNeuron 76:931-44

SLIT1 binds COL4A5

Based on studies in zebrafish, SLIT1 binds to a type IV collagen COL4A5, which forms the basement membrane on the surface of the optical tectum. COL4A5 and HSPGs may act synergistically to anchor SLIT1 in the basement membrane. ROBO2 receptor is required for lamina-specific axon pathfinding of retinal ganglion cells in the optical tectum (Xiao et al. 2011).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 204359

UniProt:O75093 SLIT1

SLIT1

MEGF4SLIL1SLIT1KIAA0813FUNCTION Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions (By similarity). SLIT1 and SLIT2 together seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb.SUBUNIT Interacts with ROBO1 and GREM1.TISSUE SPECIFICITY Predominantly expressed in adult forebrain. Expressed in fetal brain, lung and kidney.

UniProtO75093

EQUAL

1534

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2127390

Collagen alpha-5(IV) chains [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGalHyl-COL4A5 [extracellular region]GlcGalHyl-COL4A5 [extracellular region]3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]3x4Hyp-5Hyl-COL4A5 [extracellular region]3x4Hyp-3Hyp-GlcGalHyl-COL4A5 [extracellular region]3x4Hyp-3Hyp-COL4A5 [extracellular region]5Hyl-COL4A5 [extracellular region]3x4Hyp-3Hyp-5Hyl-COL4A5 [extracellular region]3x4Hyp-GalHyl-COL4A5 [extracellular region]3x4Hyp-GlcGalHyl-COL4A5 [extracellular region]3x4Hyp-COL4A5 [extracellular region]COL4A5 [extracellular region]

UniProtP29400

Reactome DB_ID: 9010400

SLIT1:COL4A5 [plasma membrane]

SLIT1:COL4A5

Reactome DB_ID: 204359

EQUAL

1534

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2127390

Reactome Database ID Release 759010400Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010400ReactomeR-HSA-9010400

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010400.1Reactome Database ID Release 759010396Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010396ReactomeR-HSA-9010396

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010396.121729787Pubmed2011Assembly of lamina-specific neuronal connections by slit bound to type IV collagenXiao, TongStaub, WendyRobles, EstuardoGosse, Nathan JCole, Gregory JBaier, HerwigCell 146:164-76

LHX2 binds to ROBO1 gene locus

Based on studies in mice, a LIM-homeodomain transcription factor LHX2 binds to evolutionarily conserved LHX2 binding elements about 30 kb downstream from the ROBO1 gene transcription start site (Marcos-Mondejar et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011093

ENSEMBL:ENSG00000169855 ROBO1DUTT1ROBO1

ENSEMBLENSG00000169855

Reactome DB_ID: 9011100

UniProt:P50458 LHX2

LHX2

LHX2LH2FUNCTION Acts as a transcriptional activator. Stimulates the promoter of the alpha-glycoprotein gene. Transcriptional regulatory protein involved in the control of cell differentiation in developing lymphoid and neural cell types (By similarity).SUBUNIT Interacts (via LIM domains) with CITED2. Interacts with POU4F2.DOMAIN LIM domains are necessary for transcription activation.

UniProtP50458

EQUAL

406

EQUAL

Reactome DB_ID: 9011114

LHX2:ROBO1 gene [nucleoplasm]

LHX2:ROBO1 gene

Reactome DB_ID: 9011093

Reactome DB_ID: 9011100

EQUAL

406

EQUAL

Reactome Database ID Release 759011114Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011114ReactomeR-HSA-9011114

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011114.1Reactome Database ID Release 759011074Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011074ReactomeR-HSA-9011074

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011074.122457488Pubmed2012The lhx2 transcription factor controls thalamocortical axonal guidance by specific regulation of robo1 and robo2 receptorsMarcos-Mondéjar, PaulaPeregrín, SandraLi, James YCarlsson, LeifTole, ShubhaLópez-Bendito, GuillerminaJ. Neurosci. 32:4372-85

ROBO1 gene expression is inhibited by LHX2

Based on studies in mice, LHX2, a LIM-homeodomain transcription factor, directly represses transcription of the ROBO1 gene by binding to evolutionarily conserved LHX2 binding sites upstream of the ROBO1 gene promoter region. LHX2 is involved in thalamocortical axon guidance (Marcos-Mondejar et al. 2012). In commissural relay neurons of the dorsal spinal cord, however, ROBO1 expression is not affected by LHX2 (Wilson et al. 2008).Transcription factors GBX2 and LMO3 may be indirectly involved in ROBO1 gene expression regulation by LHX2 (Chatterjee et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011093

Reactome DB_ID: 204361

UniProt:Q9Y6N7 ROBO1

ROBO1

DUTT1ROBO1FUNCTION Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development (PubMed:10102268, PubMed:24560577). Interaction with the intracellular domain of FLRT3 mediates axon attraction towards cells expressing NTN1 (PubMed:24560577). In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex (By similarity). Plays a role in the regulation of cell migration via its interaction with MYO9B; inhibits MYO9B-mediated stimulation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA (PubMed:26529257). May be required for lung development (By similarity).SUBUNIT Homodimer. Dimerization is mediated by the extracellular domain and is independent of SLIT liganding (PubMed:24673457). Interacts with SLIT1 (By similarity). Interacts with SLIT2 (PubMed:10102268, PubMed:11404413, PubMed:17848514). Interacts with FLRT3 (PubMed:24560577). Interacts with MYO9B (via Rho-GAP domain) (PubMed:26529257).TISSUE SPECIFICITY Widely expressed, with exception of kidney.PTM Ubiquitinated. May be deubiquitinated by USP33.MISCELLANEOUS Maps within a region of overlapping homozygous deletions characterized in both small cell lung cancer cell lines (SCLC) and in a breast cancer cell line. The promoter region of ROBO1 shows complete hypermethylation of CpG sites in the BT-20 breast tumor cell lines, some primary invasive breast carcinomasa and some primary clear cell renal cell carcinomas (CC-RCC).SIMILARITY Belongs to the immunoglobulin superfamily. ROBO family.

UniProtQ9Y6N7

EQUAL

1651

EQUAL

Reactome Database ID Release 759011083Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011083ReactomeR-HSA-9011083

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011083.218701067Pubmed2008A molecular program for contralateral trajectory: Rig-1 control by LIM homeodomain transcription factorsWilson, Sara IShafer, BethLee, Kevin JDodd, JaneNeuron 59:413-2423136391Pubmed2012Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codesChatterjee, MallikaLi, KairongChen, LiMaisano, XuGuo, QiuxiaGan, LinLi, James Y HDevelopment 139:4633-43

INHIBITION

Reactome Database ID Release 759011118Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011118ReactomeR-HSA-9011118

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011118.1

Reactome DB_ID: 9011114

USP33 deubiquitinates ROBO1

The ubiquitin protease USP33 deubiquitinates ROBO1, thus stabilizing it and increasing the concentration of ROBO1 at the plasma membrane (Yuasa-Kawada et al. 2009, Huang et al. 2015). USP33 is frequently downregulated in colorectal cancer, which is associated with lymph node metastasis and poor survival (Huang et al. 2015). USP33 is required for SLIT-ROBO1-mediated inhibition of breast cancer cell migration (Yuasa-Kawada et al. 2009). Ubiquitin ligases that ubiquitinate ROBO1 are not known.

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 29356

cytosolGO0005829

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 8986095

ubiquitinylated lysine (polyubiquitin chain [cytosol]) at unknown position

ubiquitinylated lysine [MOD:01148]

EQUAL

1651

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(77-152) [cytosol]UBB(153-228) [cytosol]UBC(305-380) [cytosol]UBB(1-76) [cytosol]UBB(77-152) [cytosol]UBA52(1-76) [cytosol]UBC(533-608) [cytosol]UBC(381-456) [cytosol]UBC(457-532) [cytosol]UBC(609-684) [cytosol]UBC(153-228) [cytosol]RPS27A(1-76) [cytosol]UBC(1-76) [cytosol]UBC(229-304) [cytosol]

UniProtP0CG48UniProtP0CG47UniProtP62987UniProtP62979

Reactome DB_ID: 204361

EQUAL

1651

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5696962

UniProt:Q8TEY7 USP33

USP33

VDU1USP33KIAA1097FUNCTION Deubiquitinating enzyme involved in various processes such as centrosome duplication, cellular migration and beta-2 adrenergic receptor/ADRB2 recycling. Involved in regulation of centrosome duplication by mediating deubiquitination of CCP110 in S and G2/M phase, leading to stabilize CCP110 during the period which centrioles duplicate and elongate. Involved in cell migration via its interaction with intracellular domain of ROBO1, leading to regulate the Slit signaling. Plays a role in commissural axon guidance cross the ventral midline of the neural tube in a Slit-dependent manner, possibly by mediating the deubiquitination of ROBO1. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination of beta-arrestins (ARRB1 and ARRB2) and beta-2 adrenergic receptor (ADRB2). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta-arrestins, leading to beta-arrestins deubiquitination and disengagement from ADRB2. This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.SUBUNIT Interacts with VHL, leading to its ubiquitination and subsequent degradation. Interacts with ARRB1, ARRB2, ADRB2, DIO2 and ROBO1. Interacts with SELENBP1; in a selenium-dependent manner. Interacts with CCP110.TISSUE SPECIFICITY Widely expressed.DEVELOPMENTAL STAGE Increased expression in S and early G2 phases and lower levels in late G2 and M phases.DOMAIN The UBP-type zinc finger binds 3 zinc ions. However, it does not bind ubiquitin, probably because the conserved Arg in position 86 is replaced by a Glu residue.PTM Ubiquitinated via a VHL-dependent pathway for proteasomal degradation.SIMILARITY Belongs to the peptidase C19 family. USP20/USP33 subfamily.

UniProtQ8TEY7

EQUAL

942

EQUAL

GO0004843

GO molecular function

Reactome Database ID Release 758986097Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8986097Reactome Database ID Release 758986083Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8986083ReactomeR-HSA-8986083

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8986083.119706539Pubmed2009Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migrationYuasa-Kawada, JunichiKinoshita-Kawada, MarikoRao, YiWu, Jane YProc. Natl. Acad. Sci. U.S.A. 106:14530-525242263Pubmed2015USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migrationHuang, ZhaohuiWen, PushuaiKong, RuiruiCheng, HaipengZhang, BinbinQuan, CaoBian, ZehuaChen, MengmengZhang, ZhenfengChen, XiaopingDu, XiangLiu, JianghongZhu, LiFushimi, KazuoHua, DongWu, Jane YInt. J. Cancer 136:1792-802

HOXA2 binds ROBO2 gene promoter

Based on studies in mice, the homeobox transcription factor HOXA2 binds to an evolutionarily conserved (also present in the human gene) HOX-PBX binding site in the second intron of the ROBO2 gene (Geisen et al. 2008). The heterodimerization partner of HOXA2 at the ROBO2 gene binding site is not known.

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9010496

ENSEMBL:ENSG00000185008 ROBO2ROBO2KIAA1568

ENSEMBLENSG00000185008

Reactome DB_ID: 5617494

UniProt:O43364 HOXA2

HOXA2

HOX1KHOXA2FUNCTION Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.SIMILARITY Belongs to the Antp homeobox family. Proboscipedia subfamily.

UniProtO43364

EQUAL

376

EQUAL

Reactome DB_ID: 9010504

HOXA2:ROBO2 gene [nucleoplasm]

HOXA2:ROBO2 gene

Reactome DB_ID: 9010496

Reactome DB_ID: 5617494

EQUAL

376

EQUAL

Reactome Database ID Release 759010504Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010504ReactomeR-HSA-9010504

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010504.1Reactome Database ID Release 759010503Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010503ReactomeR-HSA-9010503

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010503.118547144Pubmed2008Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-robo signalingGeisen, Marc JDi Meglio, ThomasPasqualetti, MassimoDucret, SebastienBrunet, Jean-FrançoisChédotal, AlainRijli, Filippo MPLoS Biol. 6:e142

LHX2 binds to ROBO2 gene locus

Based on studies in mice, a LIM-homeodomain transcription factor LHX2 binds to evolutionarily conserved LHX2 binding elements about 50 kb downstream from the ROBO2 gene transcription start site (Marcos-Mondejar et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9010496

Reactome DB_ID: 9011100

EQUAL

406

EQUAL

Reactome DB_ID: 9011108

LHX2:ROBO2 gene [nucleoplasm]

LHX2:ROBO2 gene

Reactome DB_ID: 9010496

Reactome DB_ID: 9011100

EQUAL

406

EQUAL

Reactome Database ID Release 759011108Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011108ReactomeR-HSA-9011108

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011108.1Reactome Database ID Release 759011077Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011077ReactomeR-HSA-9011077

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011077.1

ROBO2 gene transcription is stimulated by HOXA2 and inhibited by LHX2

Based on studies in mice, the homeobox transcription factor HOXA2, which directly binds to an evolutionarily conserved site in the second intron of the ROBO2 gene, is needed for the maintenance of ROBO2 expression during pontine neuron migration (Geisen et al. 2008).Also based on mouse studies, LHX2, a LIM-homeodomain transcription factor, directly represses transcription of the ROBO2 gene by binding to evolutionarily conserved LHX2 binding sites about 50 kb downstream from the ROBO2 gene transcription start site. LHX2 is involved in thalamocortical axon guidance (Marcos-Mondejar et al. 2012). In commissural relay neurons of the dorsal spinal cord, however, ROBO2 expression is not affected by LHX2 (Wilson et al. 2008).In zebrafish, transcription of Robo2 is directly stimulated by Mecp2 (Leong et al. 2015).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9010496

Reactome DB_ID: 197747

UniProt:Q9HCK4 ROBO2

ROBO2

ROBO2KIAA1568FUNCTION Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development.SUBUNIT Interacts with SLIT2.DISEASE A chromosomal aberration involving ROBO2 is a cause of multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. Translocation t(Y;3)(p11;p12) with PCDH11Y. This translocation disrupts ROBO2 and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro.SIMILARITY Belongs to the immunoglobulin superfamily. ROBO family.

UniProtQ9HCK4

EQUAL

1378

EQUAL

Reactome Database ID Release 759010523Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010523ReactomeR-HSA-9010523

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010523.226733807Pubmed2015Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2Leong, Wan YLim, Zhi HKorzh, VladimirPietri, ThomasGoh, Eyleen L KFront Cell Neurosci 9:481

INHIBITION

Reactome Database ID Release 759011104Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011104ReactomeR-HSA-9011104

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011104.1

Reactome DB_ID: 9011108

ACTIVATION

Reactome Database ID Release 759010524Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010524ReactomeR-HSA-9010524

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010524.1

Reactome DB_ID: 9010504

LHX2,(LHX9) binds the ROBO3 gene promoter

Based on studies in mice, a LIM-homeodomain transcription factor LHX2, and possibly LHX9, binds to conserved LHX2 binding elements in the promoter region of the ROBO3 gene (Wilson et al. 2008).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011166

ENSEMBL:ENSG00000154134 ROBO3ROBO3

ENSEMBLENSG00000154134Converted from EntitySet in Reactome

Reactome DB_ID: 9011165

LHX2,(LHX9) [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLHX2 [nucleoplasm]

Reactome DB_ID: 9011164

LHX2,(LHX9):ROBO3 gene [nucleoplasm]

LHX2,(LHX9):ROBO3 gene

Reactome DB_ID: 9011166

Converted from EntitySet in Reactome

Reactome DB_ID: 9011165

Reactome Database ID Release 759011164Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011164ReactomeR-HSA-9011164

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011164.1Reactome Database ID Release 759011145Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011145ReactomeR-HSA-9011145

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011145.1

ROBO3.1 expression is stimulated by LHX2,(LHX9)

Based on studies in mice, expression of the ROBO3.1 isoform from the ROBO3 gene is directly stimulated by LHX2 and possibly LHX9. LHX2/9-mediated regulation of ROBO3.1 levels is involved in midline crossing by commissural relay neurons of the dorsal spinal cord (Wilson et al. 2008). ROBO3.1 levels, however, seem to be unaffected by LHX2 in thalamocortical neurons (Marcos-Mondejar et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011166

Reactome DB_ID: 9011385

ENSEMBL:ENST00000397801 ROBO3.1ROBO3.1

ENSEMBLENST00000397801

EQUAL

4569

EQUAL

Reactome Database ID Release 759011143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011143ReactomeR-HSA-9011143

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011143.2

ACTIVATION

Reactome Database ID Release 759011163Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011163ReactomeR-HSA-9011163

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011163.1

Reactome DB_ID: 9011164

MSI1 binds ROBO3.1 mRNA

Based on studies in mice, MSI1, and RNA-binding protein, binds to ROBO3.1 mRNA (Kuwako et al. 2010).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011385

EQUAL

4569

EQUAL

Reactome DB_ID: 9011403

UniProt:O43347 MSI1

MSI1

MSI1FUNCTION RNA binding protein that regulates the expression of target mRNAs at the translation level. Regulates expression of the NOTCH1 antagonist NUMB. Binds RNA containing the sequence 5'-GUUAGUUAGUUAGUU-3' and other sequences containing the pattern 5'-[GA]U(1-3)AGU-3'. May play a role in the proliferation and maintenance of stem cells in the central nervous system (By similarity).TISSUE SPECIFICITY Detected in fetal kidney, brain, liver and lung, and in adult brain and pancreas. Detected in hepatoma cell lines.DOMAIN The first RNA recognition motif binds more strongly to RNA compared to the second one.SIMILARITY Belongs to the Musashi family.

UniProtO43347

EQUAL

362

EQUAL

Reactome DB_ID: 9011401

ROBO3.1 mRNA:MSI1 [cytosol]

ROBO3.1 mRNA:MSI1

Reactome DB_ID: 9011385

EQUAL

4569

EQUAL

Reactome DB_ID: 9011403

EQUAL

362

EQUAL

Reactome Database ID Release 759011401Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011401ReactomeR-HSA-9011401

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011401.1Reactome Database ID Release 759011346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011346ReactomeR-HSA-9011346

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011346.220696379Pubmed2010Neural RNA-binding protein Musashi1 controls midline crossing of precerebellar neurons through posttranscriptional regulation of Robo3/Rig-1 expressionKuwako, Ken-ichiroKakumoto, KyokoImai, TakaoIgarashi, ManaHamakubo, TakaoSakakibara, Shin-ichiTessier-Lavigne, MarcOkano, Hirotaka JamesOkano, HNeuron 67:407-21

ROBO3.1 mRNA translation is positively regulated by MSI1

Based on studies in mice, binding of MSI1 to ROBO3.1 mRNA positively regulates ROBO3.1 mRNA translation, resulting in increased levels of ROBO3.1 protein. Similar to Robo3 knockout mice, Msi1 knockout mice also show sever abnormalities in axonal midline crossing and migration of precerebellar neurons (Kuwako et al. 2010).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011385

EQUAL

4569

EQUAL

Reactome DB_ID: 426410

UniProt:Q96MS0-1 ROBO3

ROBO3

ROBO3FUNCTION Thought to be involved during neural development in axonal navigation at the ventral midline of the neural tube (By similarity). In spinal chord development plays a role in guiding commissural axons probably by preventing premature sensitivity to Slit proteins thus inhibiting Slit signaling through ROBO1 (By similarity). Required for hindbrain axon midline crossing (PubMed:15105459).SUBUNIT Probably interacts with SLIT2.SIMILARITY Belongs to the immunoglobulin superfamily. ROBO family.

UniProtQ96MS0-1

EQUAL

1386

EQUAL

Reactome Database ID Release 759011347Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011347ReactomeR-HSA-9011347

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011347.3

ACTIVATION

Reactome Database ID Release 759011411Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011411ReactomeR-HSA-9011411

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011411.1

Reactome DB_ID: 9011401

ZSWIM8 binds ROBO3.1

Based on studies in C. elegans and with recombinant human and mouse proteins, ZSWIM8 and its C. elegans orthologue EBAX-1 are predicted to be an E3 ubiquitin ligase component of the CUL2 ubiquitin ligase complex. ZSWIM8 co-immunoprecipitates with the CUL2 ubiquitin ligase complex components Elongin-B (ELOB) and Elongin-C (ELOC). The BC-box and Cul2-box of ZSWIM8 are needed for interaction with ELOB and ELOC, implying the presence of other CUL2 complex components in the complex of ZSWIM8, ELOB and ELOC. ZSWIM8 binds to wild-type ROBO3.1, but preferentially associates with misfolded or mutant ROBO3.1 proteins, suggesting that it is involved in the quality control of ROBO3.1 (Wang et al. 2013).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011265

ZSWIM8-CUL2 E3 ubiquitin ligase [cytosol]

ZSWIM8-CUL2 E3 ubiquitin ligase

Reactome DB_ID: 180535

UniProt:Q15369 ELOC

ELOC

TCEB1ELOCFUNCTION SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7821821). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).FUNCTION The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.SUBUNIT Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694). The elongin BC complex is part of a complex with VHL and hydroxylated HIF1A (PubMed:12050673, PubMed:12004076). Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC (PubMed:17304241). Interacts with VHL (PubMed:10205047, PubMed:12050673, PubMed:11006129). Interacts with TMF1 (PubMed:15467733). Interacts with SPSB1 (PubMed:17189197). Interacts with SPSB1. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700). Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4 (PubMed:21199876).SUBUNIT (Microbial infection) Substrate adapter protein can be a viral protein such as HIV Vif.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.TISSUE SPECIFICITY Overexpressed in prostate cancer cell line PC-3 and breast cancer cell line SK-BR-3.SIMILARITY Belongs to the SKP1 family.

UniProtQ15369

EQUAL

112

EQUAL

Reactome DB_ID: 180582

UniProt:P62877 RBX1

RBX1

RNF75ROC1RBX1FUNCTION E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair (PubMed:10230407, PubMed:10579999, PubMed:15983046, PubMed:16678110, PubMed:19112177, PubMed:19679664, PubMed:23455478, PubMed:27565346, PubMed:29769719, PubMed:11961546, PubMed:22748924). CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets (PubMed:27565346). The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2 (PubMed:11961546). Part of a SCF-like complex consisting of CUL7, RBX1, SKP1 and FBXW8. Part of CBC(VHL) complexes with elongin BC complex (ELOB and ELOC), CUL2 or CUL5 and VHL. Part of the CSA complex (DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Part of multisubunit E3 ubiquitin ligase complexes with elongin BC complex (ELOB and ELOC), CUL2 and MED8; elongin BC complex (ELOB and ELOC), CUL5 and MUF1. Part of multisubunit complexes with elongin BC complex (ELOB and ELOC), elongin A/ELOA or SOCS1 or WSB1 and CUL5. Interacts directly with CUL1 and probably also with CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7. Interacts with CDC34 (PubMed:22748924). Interacts with GLMN. GLMN competes for the binding site of the E2 ubiquitin-conjugating enzyme CDC34 and disrupts CDC34 binding (PubMed:22748924). Interacts with COPS6. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Part of an E3 ligase complex composed of RBX1, DDB1, DDB2 and CUL4A or CUL4B. Interacts with UBE2M. Part of a SCF complex consisting of CUL1, FBXO3, RBX1 and SKP1; this complex interacts with PML via FBXO3. Component of the SCF(Cyclin F) complex consisting of CUL1, RBX1, SKP1 and CCNF. Identified in a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex together with HINT1 and CDC34. Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein. Part of the BCR(ENC1) complex containing ENC1. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KLHL41) complex containing KLHL41. Part of the BCR(KEAP1) complex containing KEAP1. Interacts with DCUN1D3. Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with NOTCH2 (PubMed:29149593). Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (PubMed:23455478).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 protein E1A; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBW7) complex.TISSUE SPECIFICITY Widely expressed.DOMAIN The RING-type zinc finger domain is essential for ubiquitin ligase activity (PubMed:10230407). It coordinates an additional third zinc ion (PubMed:11961546, PubMed:22748924).SIMILARITY Belongs to the RING-box family.

UniProtP62877

EQUAL

108

EQUAL

Reactome DB_ID: 9011266

UniProt:A7E2V4 ZSWIM8

ZSWIM8

ZSWIM8KIAA0913SIMILARITY Contains 1 SWIM-type zinc finger.

UniProtA7E2V4

EQUAL

1837

EQUAL

Reactome DB_ID: 180551

UniProt:Q15370 ELOB

ELOB

TCEB2ELOBFUNCTION SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7638163). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).FUNCTION The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterotrimer of an A (ELOA, ELOA2 or ELOA3), ELOB and ELOC subunit (PubMed:10205047, PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694, PubMed:22286099). Interacts with VHL (PubMed:10205047, PubMed:11006129). Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with SPSB1 (PubMed:17189197). Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700).SUBUNIT (Microbial infection) Substrate adapter protein can be a viral protein such as HIV Vif.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.

UniProtQ15370

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118

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Reactome DB_ID: 416982

UniProt:Q13617 CUL2

CUL2

CUL2FUNCTION Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). May serve as a rigid scaffold in the complex and may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the ECS complex depends on the substrate recognition component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes formed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and a variable substrate-specific adapter. Component of the ECS(VHL) or CBC(VHL) complex containing VHL. Component of the ECS(MED8) complex with the probable substrate recognition component MED8. Component of the ECS(LRR1) complex with the probable substrate recognition component LRR1. Component of a probable ECS E3 ubiquitin-protein ligase complex containing CUL2, RBX1, ELOB, ELOC and FEM1B. Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC. Interacts with RBX1, RNF7, FEM1B and TIP120A/CAND1. Interacts with COPS2, and MED8. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346).SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.PTM Neddylated; which enhances the ubiquitination activity of ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes. CBC(VHL) complex formation seems to promote neddylation. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (By similarity).SIMILARITY Belongs to the cullin family.

UniProtQ13617

EQUAL

745

EQUAL

Reactome Database ID Release 759011265Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011265ReactomeR-HSA-9011265

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011265.1

Reactome DB_ID: 426410

EQUAL

1386

EQUAL

Reactome DB_ID: 9011286

ROBO3.1:ZSWIM8-CUL2 [plasma membrane]

ROBO3.1:ZSWIM8-CUL2

Reactome DB_ID: 9011265

Reactome DB_ID: 426410

EQUAL

1386

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Reactome Database ID Release 759011286Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011286ReactomeR-HSA-9011286

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011286.1Reactome Database ID Release 759011289Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011289ReactomeR-HSA-9011289

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011289.224012004Pubmed2013The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neuronsWang, ZhipingHou, YanliGuo, Xingvan der Voet, MoniqueBoxem, MikeDixon, JEChisholm, Andrew DJin, YishiNeuron 79:903-16

ZSWIM8 ubiquitinates ROBO3.1

Based on studies with C. elegans proteins, ZSWIM8 (orthologue of C. elegans EBAX-1) promotes ubiquitination of ROBO3.1 (orthologue of C. elegans SAX-3) (Wang et al. 2013).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011286

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 9011309

Ub-ROBO3.1:ZSWIM8-CUL2 [plasma membrane]

Ub-ROBO3.1:ZSWIM8-CUL2

Reactome DB_ID: 9011265

Reactome DB_ID: 9011301

ubiquitinylated lysine (Ub [cytosol]) at unknown position

EQUAL

1386

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Reactome Database ID Release 759011309Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011309ReactomeR-HSA-9011309

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011309.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9011286

GO0061630

GO molecular function

Reactome Database ID Release 759011307Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011307Reactome Database ID Release 759011300Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011300ReactomeR-HSA-9011300

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011300.1

Proteasome degrades ubiquitinated ROBO3.1

Based on studies using recombinant C. elegans proteins expressed in human 293T cells, ZSWIM8-mediated ubiquitination of ROBO3.1 targets ROBO3.1 for proteasome-mediated degradation (Wang et al. 2013).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011309

Reactome DB_ID: 9011265

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 68819

26S proteasome [cytosol]

26S proteasome

Reactome DB_ID: 68800

UniProt:P55036 PSMD4

PSMD4

MCB1PSMD4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family.

UniProtP55036

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377

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Reactome DB_ID: 68802

UniProt:Q16401 PSMD5

PSMD5

PSMD5KIAA0072FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome.

UniProtQ16401

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504

EQUAL

Reactome DB_ID: 68810

UniProt:O00233 PSMD9

PSMD9

PSMD9FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome.

UniProtO00233

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223

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Reactome DB_ID: 947607

UniProt:A5LHX3 PSMB11

PSMB11

PSMB11FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family.

UniProtA5LHX3

EQUAL

300

EQUAL

Reactome DB_ID: 947610

UniProt:Q8TAA3 PSMA8

PSMA8

PSMA7LPSMA8FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complexe that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.SIMILARITY Belongs to the peptidase T1A family.

UniProtQ8TAA3

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256

EQUAL

Reactome DB_ID: 68771

UniProt:P35998 PSMC2

PSMC2

MSS1PSMC2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.SIMILARITY Belongs to the AAA ATPase family.

UniProtP35998

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433

EQUAL

Reactome DB_ID: 68804

UniProt:Q15008 PSMD6

PSMD6

PSMD6KIAA0107PFAAP4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family.

UniProtQ15008

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389

EQUAL

Reactome DB_ID: 947606

UniProt:Q14997 PSME4

PSME4

PSME4KIAA0077FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family.

UniProtQ14997

EQUAL

1843

EQUAL

Reactome DB_ID: 68786

UniProt:Q99460 PSMD1

PSMD1

PSMD1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family.

UniProtQ99460

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953

EQUAL

Reactome DB_ID: 68798

UniProt:O43242 PSMD3

PSMD3

PSMD3FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family.

UniProtO43242

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534

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Reactome DB_ID: 68814

UniProt:Q9UL46 PSME2

PSME2

PSME2FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ9UL46

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239

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Reactome DB_ID: 8866674

UniProt:P60896 SEM1

SEM1

SEM1C7orf76SHFDG1SHFM1DSS1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family.

UniProtP60896

EQUAL

Reactome DB_ID: 68765

UniProt:P28065 PSMB9

PSMB9

LMP2PSMB6iRING12PSMB9FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28065

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219

EQUAL

Reactome DB_ID: 68792

UniProt:O00232 PSMD12

PSMD12

PSMD12FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family.

UniProtO00232

EQUAL

456

EQUAL

Reactome DB_ID: 68818

UniProt:Q92530 PSMF1

PSMF1

PSMF1FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family.

UniProtQ92530

EQUAL

271

EQUAL

Reactome DB_ID: 68732

UniProt:P28066 PSMA5

PSMA5

PSMA5FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family.

UniProtP28066

EQUAL

241

EQUAL

Reactome DB_ID: 68777

UniProt:P43686 PSMC4

PSMC4

TBP7PSMC4MIP224FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family.

UniProtP43686

EQUAL

418

EQUAL

Reactome DB_ID: 68759

UniProt:Q99436 PSMB7

PSMB7

PSMB7ZFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family.

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UniProt:P62195 PSMC5

PSMC5

PSMC5SUG1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family.

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Reactome DB_ID: 68816

UniProt:P61289 PSME3

PSME3

PSME3FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family.

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Reactome DB_ID: 68736

UniProt:O14818 PSMA7

PSMA7

PSMA7HSPCFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68774

UniProt:P17980 PSMC3

PSMC3

PSMC3TBP1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family.

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Reactome DB_ID: 68768

UniProt:P62191 PSMC1

PSMC1

PSMC1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.

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Reactome DB_ID: 68794

UniProt:Q9UNM6 PSMD13

PSMD13

PSMD13FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family.

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Reactome DB_ID: 68724

UniProt:P25786 PSMA1

PSMA1

PSMA1HC2NUPSC2PROS30FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68726

UniProt:P25787 PSMA2

PSMA2

PSMA2PSC3HC3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68728

UniProt:P25788 PSMA3

PSMA3

PSMA3HC8PSC8FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68788

UniProt:O75832 PSMD10

PSMD10

PSMD10FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome.

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Reactome DB_ID: 68730

UniProt:P25789 PSMA4

PSMA4

PSMA4PSC9HC9FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68734

UniProt:P60900 PSMA6

PSMA6

PSMA6PROS27FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68750

UniProt:P28070 PSMB4

PSMB4

PSMB4PROS26FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.

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Reactome DB_ID: 68762

UniProt:P28062 PSMB8

PSMB8

PSMB5iRING10Y2LMP7PSMB8FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68796

UniProt:Q13200 PSMD2

PSMD2

TRAP2PSMD2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family.

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Reactome DB_ID: 68722

UniProt:O00487 PSMD14

PSMD14

PSMD14POH1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily.

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Reactome DB_ID: 68756

UniProt:P28072 PSMB6

PSMB6

PSMB6LMPYYFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68738

UniProt:P20618 PSMB1

PSMB1

PSC5PSMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68806

UniProt:P51665 PSMD7

PSMD7

MOV34LPSMD7FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family.

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Reactome DB_ID: 68790

UniProt:O00231 PSMD11

PSMD11

PSMD11FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family.

UniProtO00231

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Reactome DB_ID: 68744

UniProt:P49721 PSMB2

PSMB2

PSMB2FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68741

UniProt:P40306 PSMB10

PSMB10

LMP10MECL1PSMB10FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68783

UniProt:P62333 PSMC6

PSMC6

PSMC6SUG2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924.

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Reactome DB_ID: 68808

UniProt:P48556 PSMD8

PSMD8

PSMD8FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator.

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Reactome DB_ID: 68812

UniProt:Q06323 PSME1

PSME1

PSME1IFI5111FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ06323

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Reactome DB_ID: 68747

UniProt:P49720 PSMB3

PSMB3

PSMB3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family.

UniProtP49720

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Reactome DB_ID: 68753

UniProt:P28074 PSMB5

PSMB5

PSMB5XLMPXMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family.

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Reactome Database ID Release 7568819Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68819ReactomeR-HSA-68819

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68819.2GO0004175

GO molecular function

Reactome Database ID Release 7568824Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68824Reactome Database ID Release 759011313Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011313ReactomeR-HSA-9011313

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011313.1

Transcription of ROBO3.2 mRNA

Based on studies in mice, a transcript variant ROBO3.2 is produced from nascent ROBO3 mRNA by alternative splicing. Existence of this splicing isoform is predicted to be conserved in humans and rats. The alternative splicing results in retention of the intronic sequence between exons 26 and 27, which creates a premature stop codon. While Robo3.1 mouse mRNA is expressed in the pre-crossing and crossing commissural axons, Robo3.2 mRNA is expressed after midline crossing and thought to block midline re-crossing (Chen et al. 2008).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9011166

Reactome DB_ID: 9014585

ROBO3.2 mRNA [cytosol]

ROBO3.2 mRNA

Reactome Database ID Release 759014587Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014587ReactomeR-HSA-9014587

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014587.118466743Pubmed2008Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsionChen, ZGore, BBLong, HMa, LTessier-Lavigne, MNeuron 58:325-32

Translation of ROBO3.2 mRNA initiates NMD

Based on studies in mice, ROBO3.2 mRNA, which contains a premature stop codon, is recognized by components of the nonsense mediated decay (NMD) machinery during translation. Association of ROBO3.2 mRNA with UPF2 and UPF1 was directly demonstrated in mouse cells, and presence of other translation and NMD components is assumed (Colak et al. 2013). In this step, we only show association of ROBO3.2 mRNA with the UPF2-containing exon junction complex. For detailed representation of UPF2 and UPF1 in NMD, please refer to the Reactome pathway 'Nonsense Mediated Decay (NMD)'.

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 927798

Exon Junction:UPF2:UPF3 Complex [cytosol]

Exon Junction:UPF2:UPF3 Complex

Reactome DB_ID: 927869

Core Exon Junction Complex (Core EJC) [cytosol]

Core Exon Junction Complex (Core EJC)

Reactome DB_ID: 927807

UniProt:O15234 CASC3

CASC3

CASC3MLN51FUNCTION Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Stimulates the ATPase and RNA-helicase activities of EIF4A3. Plays a role in the stress response by participating in cytoplasmic stress granules assembly and by favoring cell recovery following stress. Component of the dendritic ribonucleoprotein particles (RNPs) in hippocampal neurons. May play a role in mRNA transport. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Binds poly(G) and poly(U) RNA homopolymer.SUBUNIT Identified in the spliceosome C complex (PubMed:28502770, PubMed:29301961). Component of the mRNA splicing-dependent exon junction complex (EJC), which contains at least CASC3, EIF4A3, MAGOH, NXF1 and RBM8A/Y14 (PubMed:15166247, PubMed:16170325, PubMed:16314458, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (PubMed:20479275). Forms homooligomers (By similarity). Interacts with STAU in an RNA-dependent manner (By similarity).TISSUE SPECIFICITY Widely expressed. Overexpressed in breast cancers and metastasis, as well as in gastric cancers.DOMAIN The coiled coil domain may be involved in oligomerization.PTM ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination.PTM Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation.SIMILARITY Belongs to the CASC3 family.

UniProtO15234

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Reactome DB_ID: 927868

UniProt:P38919 EIF4A3

EIF4A3

DDX48EIF4A3KIAA0111FUNCTION ATP-dependent RNA helicase (PubMed:16170325). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs (PubMed:16209946, PubMed:16170325, PubMed:16314458, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly (PubMed:22203037). Involved in craniofacial development (PubMed:24360810).ACTIVITY REGULATION The ATPase activity is increased some 4-fold in the presence of RNA.SUBUNIT Identified in the spliceosome C complex (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346, PubMed:29301961). Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A (PubMed:15034551, PubMed:14730019, PubMed:16170325, PubMed:16314458, PubMed:23917022, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Interacts with CASC3, MAGOH, NXF1, RBM8A and ALYREF/THOC4 (PubMed:14730019, PubMed:16170325, PubMed:16495234, PubMed:22961380). May interact with NOM1. Interacts with POLDIP3 (PubMed:18423201). Interacts with CWC22 and PRPF19 in an RNA-independent manner (PubMed:22959432, PubMed:22961380, PubMed:23236153, PubMed:24218557). Direct interaction with CWC22 is mediated by the helicase C-terminal domain (PubMed:22959432, PubMed:24218557). Full interaction with CWC22 occurs only when EIF4A3 is not part of the EJC and prevents EIF4A3 binding to RNA. Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (PubMed:20479275). Interacts with NCBP3 (PubMed:26382858).TISSUE SPECIFICITY Ubiquitously expressed.SIMILARITY Belongs to the DEAD box helicase family. eIF4A subfamily.

UniProtP38919

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Reactome DB_ID: 162463

Magoh-Y14 complex [cytosol]

Magoh-Y14 complex

Reactome DB_ID: 162462

UniProt:Q9Y5S9 RBM8A

RBM8A

RBM8ARBM8MDS014HSPC114FUNCTION Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. The MAGOH-RBM8A heterodimer is a component of the nonsense mediated decay (NMD) pathway. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly.SUBUNIT Heterodimer with either MAGOH or MAGOHB (PubMed:10662555, PubMed:12730685, PubMed:23917022, PubMed:12781131). Part of the mRNA splicing-dependent exon junction complex (EJC) complex; the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A (PubMed:11707413, PubMed:16170325, PubMed:16314458, PubMed:23917022, PubMed:16923391, PubMed:16931718, PubMed:19033377, PubMed:20479275). Interacts with PYM1; the interaction is direct and dissociates the EJC from spliced mRNAs (PubMed:14968132, PubMed:18026120, PubMed:19410547). Part of a complex that contains the EJC core components CASC3, EIF4A3, MAGOH and RBM8A plus proteins involved in nonsense-mediated mRNA decay, such as UPF1, UPF2, UPF3A and UPF3B (PubMed:11546873, PubMed:12718880, PubMed:20479275). Found in a post-splicing complex with NXF1, MAGOH, UPF1, UPF2, UPF3A, UPF3B and RNPS1 (PubMed:11546874). Interacts with BAT1, MAGOH, DPH1, UPF3B, RNPS1, SRRM1 and ALYREF/THOC4 (PubMed:11013075, PubMed:11118221, PubMed:11707413, PubMed:12944400). Interacts with IPO13; the interaction mediates the nuclear import of the MAGOH-RBM8A heterodimer (PubMed:11447110). Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:29301961). Associates with polysomes (PubMed:12121612).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the RBM8A family.

UniProtQ9Y5S9

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174

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Converted from EntitySet in Reactome

Reactome DB_ID: 8868752

MAGOH,MAGOHB [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAGOHB [nucleoplasm]MAGOH [nucleoplasm]

UniProtQ96A72UniProtP61326Reactome Database ID Release 75162463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162463ReactomeR-HSA-162463

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-162463.2Reactome Database ID Release 75927869Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=927869ReactomeR-HSA-927869

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-927869.1

Reactome DB_ID: 159256

UniProt:Q15287 RNPS1

RNPS1

LDC2RNPS1FUNCTION Part of pre- and post-splicing multiprotein mRNP complexes. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit RNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Enhances the formation of the ATP-dependent A complex of the spliceosome. Involved in both constitutive splicing and, in association with SRP54 and TRA2B/SFRS10, in distinctive modulation of alternative splicing in a substrate-dependent manner. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function. Participates in mRNA 3'-end cleavage. Involved in UPF2-dependent nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Also mediates increase of mRNA abundance and translational efficiency. Binds spliced mRNA 20-25 nt upstream of exon-exon junctions.SUBUNIT Found in mRNA splicing-dependent exon junction complexes (EJC). Found in a post-splicing complex with NXF1, RBM8A, UPF1, UPF2, UPF3A, UPF3B and RNPS1. Component of the heterotrimeric ASAP (apoptosis- and splicing-associated protein) and PSAP complexes consisting of RNPS1, SAP18 and either ACIN1 or PNN, respectively; the ASAP and PSAP complexes probably are formed mutually exclusive. Component of the active spliceosome. Associates with polysomes. Interacts with the cleaved p110 isoform of CDC2L1, CSNK2A1, PNN, SART3, SRP54, SRRM1 and TRA2B/SFRS10.TISSUE SPECIFICITY Ubiquitous.DOMAIN The RRM domain is required for the formation of the ASAP complex.PTM Phosphorylated on one or more of the four Ser/Thr residues (Ser-43, Thr-49, Ser-52 or Ser-53). Ser-53 phosphorylation site is important for splicing and translation stimulation activity in vitro.SIMILARITY Belongs to the splicing factor SR family.

UniProtQ15287

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Reactome DB_ID: 927799

UniProt:Q9HAU5 UPF2

UPF2

UPF2KIAA1408RENT2FUNCTION Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC). Recruited by UPF3B associated with the EJC core at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2-UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. In cooperation with UPF3B stimulates both ATPase and RNA helicase activities of UPF1. Binds spliced mRNA.SUBUNIT Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Associates with the exon junction complex (EJC). Interacts with SMG1, EST1A, UPF1, UPF3A, UPF3B, EIF4A1 and EIF1.TISSUE SPECIFICITY Ubiquitous.

UniProtQ9HAU5

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1272

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Converted from EntitySet in Reactome

Reactome DB_ID: 927833

UPF3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUPF3B [cytosol]UPF3A [cytosol]

UniProtQ9BZI7UniProtQ9H1J1Reactome Database ID Release 75927798Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=927798ReactomeR-HSA-927798

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-927798.1

Reactome DB_ID: 54433

UniProt:P62495 ETF1

ETF1

SUP45L1ERF1ETF1RF1FUNCTION Directs the termination of nascent peptide synthesis (translation) in response to the termination codons UAA, UAG and UGA (PubMed:7990965, PubMed:24486019). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes (PubMed:30682371).SUBUNIT Heterodimer of two subunits, one of which binds GTP (PubMed:19417104). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (PubMed:19417104). Interacts with JMJD4 (PubMed:24486019). The ETF1-GSPT1 complex interacts with JMJD4 (PubMed:24486019).PTM Methylated at Gln-185 by N6AMT1.PTM Hydroxylation at Lys-63 by JMJD4 promotes its translational termination efficiency.SIMILARITY Belongs to the eukaryotic release factor 1 family.

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Reactome DB_ID: 162460

Cap Binding Complex (CBC) [cytosol]

Cap Binding Complex (CBC)

Reactome DB_ID: 162459

UniProt:Q09161 NCBP1

NCBP1

NCBP1CBP80NCBPFUNCTION Component of the cap-binding complex (CBC), which binds cotranscriptionally to the 5'-cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5'-end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2 and is required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP1/CBP80 does not bind directly capped RNAs (m7GpppG-capped RNA) but is required to stabilize the movement of the N-terminal loop of NCBP2/CBP20 and lock the CBC into a high affinity cap-binding state with the cap structure. Associates with NCBP3 to form an alternative cap-binding complex (CBC) which plays a key role in mRNA export and is particularly important in cellular stress situations such as virus infections. The conventional CBC with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus whereas the alternative CBC with NCBP3 does not bind snRNA and associates only with mRNA thereby playing a role only in mRNA export. NCBP1/CBP80 is required for cell growth and viability (PubMed:26382858).SUBUNIT Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA. Found in a U snRNA export complex containing PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with PHAX/RNUXA, SRRT/ARS2, EIF4G2, IGF2BP1, HNRNPF, HNRNPH1, KIAA0427/CTIF, PARN, DROSHA, UPF1 and ALYREF/THOC4. May interact with EIF4G1; the interaction is however controversial since it is reported by PubMed:11340157, PubMed:15059963 and PubMed:15361857, but is not observed by PubMed:19648179. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1/CBP80 and POLR2A. Component of an alternative nuclear cap-binding complex (CBC) composed of NCBP1/CBP80 and NCBP3 (PubMed:26382858). Interacts with METTL3 (PubMed:27117702). Interacts with ZFC3H1 in a RNase-insensitive manner (PubMed:27871484). Interacts with MTREX (PubMed:30842217). Interacts with TASOR (By similarity).SIMILARITY Belongs to the NCBP1 family.

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Reactome DB_ID: 162458

UniProt:P52298 NCBP2

NCBP2

CBP20NCBP2PIG55FUNCTION Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure. The conventional cap-binding complex with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus (PubMed:26382858).SUBUNIT Component of the nuclear cap-binding complex (CBC), a heterodimer composed of NCBP1/CBP80 and NCBP2/CBP20 that interacts with m7GpppG-capped RNA (PubMed:26382858). Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Interacts with PHAX/RNUXA, EIF4G1, HNRNPF, HNRNPH1 and ALYREF/THOC4/ALY. Interacts with SRRT/ARS2 and KPNA3 (PubMed:26382858).SIMILARITY Belongs to the RRM NCBP2 family.

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Reactome Database ID Release 75162460Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162460ReactomeR-HSA-162460

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-162460.1

Reactome DB_ID: 156803

UniProt:P11940 PABPC1

PABPC1

PAB1PABP1PABPC2PABPC1FUNCTION Binds the poly(A) tail of mRNA, including that of its own transcript, and regulates processes of mRNA metabolism such as pre-mRNA splicing and mRNA stability (PubMed:11051545, PubMed:17212783, PubMed:25480299). Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2 (PubMed:11051545, PubMed:20573744). Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Involved in translationally coupled mRNA turnover (PubMed:11051545). Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain (PubMed:11051545). Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed (PubMed:18447585). By binding to long poly(A) tails, may protect them from uridylation by ZCCHC6/ZCCHC11 and hence contribute to mRNA stability (PubMed:25480299).FUNCTION (Microbial infection) Positively regulates the replication of dengue virus (DENV).SUBUNIT May interact with SETX (PubMed:21700224). May form homodimers. Component of a multisubunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1 (PubMed:16356927). Directly interacts with IGF2BP1. Part of a complex associated with the FOS mCRD domain and consisting of HNRPD, SYNCRIP, PAIP1 and CSDE1/UNR (PubMed:11051545). Interacts with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1 and PAIP2 (PubMed:9548260, PubMed:11172725, PubMed:11438674, PubMed:11997512, PubMed:11287632, PubMed:20096703). Interacts with PAIP1 with a 1:1 stoichiometry and with PAIP2 with a 1:2 stoichiometry. The interaction with CSDE1 is direct and RNA-independent. Found in a mRNP complex with YBX2 (By similarity). Interacts with TENT2/GLD2 (By similarity). Identified in the spliceosome C complex (PubMed:11991638). Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. The interaction with DDX3X is direct and RNA-independent (PubMed:18596238, PubMed:21883093, PubMed:22872150). This interaction increases in stressed cells and decreases during cell recovery (PubMed:21883093). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with NXF1/TAP (PubMed:17267499, PubMed:18596238). Interacts with PIWIL1 (By similarity). Interacts with AGO1, AGO2, GSPT1 and GSPT2 (PubMed:17932509, PubMed:18447585, Ref.57). Interacts with LARP4B (Ref.59). Interacts (via the second and third RRM domains and the C-terminus) with PAIP2B (via central acidic portion and C-terminus) (PubMed:16804161, PubMed:11287632). Forms a complex with LARP1 and SHFL (PubMed:20430826, PubMed:24532714, PubMed:25940091, PubMed:26735137). Interacts with LARP4 (PubMed:21098120). Interacts with ZFC3H1 in a RNase-sensitive manner (PubMed:27871484). Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with TENT5C; the interaction has no effect on TENT5C poly(A) polymerase function (PubMed:28931820). Interacts with G3BP1 and G3BP2 (PubMed:23279204). Interacts with ENDOV; the interaction is RNA-dependent and stimulates ENDOV activity (PubMed:27573237).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL69.TISSUE SPECIFICITY Ubiquitous.DOMAIN The RNA-binding domains RRM1 and RRM2 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP1, respectively.DOMAIN The RNA-binding domains RRM2 and RRM3 and the C-terminus (last 138 amino acids) regions interact with the PABPC1-interacting motif-1 (PAM1) and -2 (PAM2) of PAIP2, respectively.PTM Phosphorylated by MAPKAPK2.PTM Methylated by CARM1. Arg-493 is dimethylated, probably to asymmetric dimethylarginine.MISCELLANEOUS Many viruses shutoff host mRNA translational machinery by inhibiting cellular PABPC1 activity using different mechanisms. Picornaviruses, caliciviruses or lentiviruses encode proteases that cleave PABPC1 at several defined sites in the proline-rich linker region between RRMs and the C-terminal domain. Rotaviruses, gammherpesviruses and bunyamwera virus relocalize PABPC1 from the cytoplasm to the nucleus thus altering its function. Many of these viruses translate their mRNA in a PABPC1-independent manner and are unaffected by host PABPC1 inhibition.SIMILARITY Belongs to the polyadenylate-binding protein type-1 family.CAUTION Was termed (Ref.5) polyadenylate binding protein II.

UniProtP11940

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Reactome DB_ID: 143378

eRF3:GDP [cytosol]

eRF3:GDP

Reactome DB_ID: 29420

GDP [ChEBI:17552]

GDP

Guanosine 5'-diphosphateGuanosine diphosphate

ChEBI17552Converted from EntitySet in Reactome

Reactome DB_ID: 8865793

eRF3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGSPT1 [cytosol]GSPT2 [cytosol]

UniProtP15170UniProtQ8IYD1Reactome Database ID Release 75143378Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=143378ReactomeR-HSA-143378

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-143378.2

Reactome DB_ID: 9014585

Reactome DB_ID: 72500

80S ribosome [cytosol]

80S ribosome

80S monosome

Reactome DB_ID: 72392

40S ribosomal complex [cytosol]

40S ribosomal complex

Reactome DB_ID: 72387

UniProt:P46781 RPS9

RPS9

RPS9SUBUNIT Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs.SIMILARITY Belongs to the universal ribosomal protein uS4 family.

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Reactome DB_ID: 72367

UniProt:P62273 RPS29

RPS29

RPS29SUBUNIT Component of the 40S small ribosomal subunit.SIMILARITY Belongs to the universal ribosomal protein uS14 family.

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Reactome DB_ID: 72369

UniProt:P23396 RPS3

RPS3

OK/SW-cl.26RPS3FUNCTION Involved in translation as a component of the 40S small ribosomal subunit (PubMed:8706699). Has endonuclease activity and plays a role in repair of damaged DNA (PubMed:7775413). Cleaves phosphodiester bonds of DNAs containing altered bases with broad specificity and cleaves supercoiled DNA more efficiently than relaxed DNA (PubMed:15707971). Displays high binding affinity for 7,8-dihydro-8-oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species (ROS) (PubMed:14706345). Has also been shown to bind with similar affinity to intact and damaged DNA (PubMed:18610840). Stimulates the N-glycosylase activity of the base excision protein OGG1 (PubMed:15518571). Enhances the uracil excision activity of UNG1 (PubMed:18973764). Also stimulates the cleavage of the phosphodiester backbone by APEX1 (PubMed:18973764). When located in the mitochondrion, reduces cellular ROS levels and mitochondrial DNA damage (PubMed:23911537). Has also been shown to negatively regulate DNA repair in cells exposed to hydrogen peroxide (PubMed:17049931). Plays a role in regulating transcription as part of the NF-kappa-B p65-p50 complex where it binds to the RELA/p65 subunit, enhances binding of the complex to DNA and promotes transcription of target genes (PubMed:18045535). Represses its own translation by binding to its cognate mRNA (PubMed:20217897). Binds to and protects TP53/p53 from MDM2-mediated ubiquitination (PubMed:19656744). Involved in spindle formation and chromosome movement during mitosis by regulating microtubule polymerization (PubMed:23131551). Involved in induction of apoptosis through its role in activation of CASP8 (PubMed:14988002). Induces neuronal apoptosis by interacting with the E2F1 transcription factor and acting synergistically with it to up-regulate pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5 (PubMed:20605787). Interacts with TRADD following exposure to UV radiation and induces apoptosis by caspase-dependent JNK activation (PubMed:22510408).ACTIVITY REGULATION Endonuclease activity is inhibited by MgCl2 on apurinic/apyrimidinic DNA but not on UV-irradiated DNA.SUBUNIT Component of the 40S small ribosomal subunit (PubMed:8706699). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with HNRPD (PubMed:24423872). Interacts with PRMT1; the interaction methylates RPS3 (PubMed:19460357). Interacts with SUMO1; the interaction sumoylates RPS3 (PubMed:21968017). Interacts with UBC9 (PubMed:21968017). Interacts with CDK1; the interaction phosphorylates RPS3 (PubMed:21871177). Interacts with PRKCD; the interaction phosphorylates RPS3 (PubMed:19059439). Interacts with PKB/AKT; the interaction phosphorylates RPS3 (PubMed:20605787). Interacts with E2F1; the interaction occurs in the absence of nerve growth factor and increases transcription of pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5 (PubMed:20605787). Interacts with the base excision repair proteins APEX1 and OGG1; interaction with OGG1 increases OGG1 N-glycosylase activity (PubMed:15518571). Interacts with UNG; the interaction increases the uracil excision activity of UNG1 (PubMed:18973764). Interacts with HSP90; the interaction prevents the ubiquitination and proteasome-dependent degradation of RPS3 and is suppressed by increased ROS levels (PubMed:16314389). Interacts with TOM70; the interaction promotes translocation of RPS3 to the mitochondrion (PubMed:23911537). Interacts (via N-terminus) with RELA (via N-terminus); the interaction enhances the DNA-binding activity of the NF-kappa-B p65-p50 complex (PubMed:18045535). Interacts with NFKBIA; the interaction is direct and may bridge the interaction between RPS3 and RELA (PubMed:24457201). Interacts with IKKB; the interaction phosphorylates RPS3 and enhances its translocation to the nucleus (PubMed:21399639). Interacts (via KH domain) with MDM2 and TP53 (PubMed:19656744). Interacts with TRADD (PubMed:22510408). Interacts (via N-terminus) with E.coli O157:H7 (strain EDL933) nleH1 and nleH2; the interaction with nleH1 inhibits phosphorylation by IKKB, reduces RPS3 nuclear abundance and inhibits transcriptional activation by the NF-kappa-B p65-p50 complex (PubMed:20041225, PubMed:21399639). Identified in a HCV IRES-mediated translation complex, at least composed of EIF3C, IGF2BP1, RPS3 and HCV RNA-replicon (PubMed:19541769). Interacts with CRY1 (By similarity).PTM Methylation by PRMT1 is required for import into the nucleolus and for ribosome assembly.PTM Sumoylation by SUMO1 enhances protein stability through increased resistance to proteolysis. Sumoylation occurs at one or more of the three consensus sites, Lys-18, Lys-214 and Lys-230.PTM Phosphorylation at Thr-221 by CDK1 occurs mainly in G2/M phase (PubMed:21871177). Phosphorylation by PRKCD occurs on a non-ribosomal-associated form which results in translocation of RPS3 to the nucleus and enhances its endonuclease activity (PubMed:19059439). Phosphorylated on Ser-209 by IKKB in response to activation of the NF-kappa-B p65-p50 complex which enhances the association of RPS3 with importin-alpha and mediates the nuclear translocation of RPS3 (PubMed:21399639). Phosphorylation by MAPK is required for translocation to the nucleus following exposure of cells to DNA damaging agents such as hydrogen peroxide (PubMed:17560175). Phosphorylation by PKB/AKT mediates RPS3 nuclear translocation, enhances RPS3 endonuclease activity and suppresses RPS3-induced neuronal apoptosis (PubMed:20605787).PTM Ubiquitinated (PubMed:16314389). This is prevented by interaction with HSP90 which stabilizes the protein (PubMed:16314389). Monoubiquitinated at Lys-214 by ZNF598 when a ribosome has stalled during translation of poly(A) sequences, leading to preclude synthesis of a long poly-lysine tail and initiate the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843).PTM Ufmylated by UFL1.SIMILARITY Belongs to the universal ribosomal protein uS3 family.

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Reactome DB_ID: 72383

UniProt:P62081 RPS7

RPS7

RPS7FUNCTION Required for rRNA maturation.SUBUNIT Binds IPO9 with high affinity (PubMed:11823430). Interacts with NEK6 (PubMed:20873783). Interacts with DESI2 (PubMed:28483520).PTM Phosphorylated by NEK6.PTM Ubiquitinated. Deubiquitinated by DESI2, leading to its stabilization.SIMILARITY Belongs to the eukaryotic ribosomal protein eS7 family.

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Reactome DB_ID: 72349

UniProt:P60866 RPS20

RPS20

RPS20SUBUNIT Component of the 40S small ribosomal subunit.PTM Monoubiquitinated by ZNF598 when a ribosome has stalled during translation of poly(A) sequences, leading to preclude synthesis of a long poly-lysine tail and initiate the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843).PTM Ufmylated by UFL1.SIMILARITY Belongs to the universal ribosomal protein uS10 family.

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Reactome DB_ID: 72325

UniProt:P46783 RPS10

RPS10

RPS10FUNCTION Component of the 40S ribosomal subunit.SUBUNIT Component of the small ribosomal subunit. Interacts with PRMT5. The methylated form interacts with NPM1.PTM Methylated by PRMT5. Methylation is necessary for its interaction with NPS1, its localization in the granular component (GC) region of the nucleolus, for the proper assembly of ribosomes, protein synthesis and optimal cell proliferation.PTM Monoubiquitinated by ZNF598 when a ribosome has stalled during translation of poly(A) sequences, leading to preclude synthesis of a long poly-lysine tail and initiate the ribosome quality control (RQC) pathway to degrade the potentially detrimental aberrant nascent polypeptide (PubMed:28065601, PubMed:28132843).SIMILARITY Belongs to the eukaryotic ribosomal protein eS10 family.

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Reactome DB_ID: 72339

UniProt:P08708 RPS17

RPS17

RPS17RPS17LSIMILARITY Belongs to the eukaryotic ribosomal protein eS17 family.

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Reactome DB_ID: 72359

UniProt:P62854 RPS26

RPS26

RPS26SUBUNIT Component of the 40S small ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eS26 family.

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115

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Reactome DB_ID: 72331

UniProt:P62277 RPS13

RPS13

RPS13SIMILARITY Belongs to the universal ribosomal protein uS15 family.

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151

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Reactome DB_ID: 72389

UniProt:P08865 RPSA

RPSA

LAMBRRPSALAMR1FUNCTION Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Also functions as a cell surface receptor for laminin. Plays a role in cell adhesion to the basement membrane and in the consequent activation of signaling transduction pathways. May play a role in cell fate determination and tissue morphogenesis. Acts as a PPP1R16B-dependent substrate of PPP1CA.FUNCTION (Microbial infection) Acts as a receptor for the Adeno-associated viruses 2,3,8 and 9.FUNCTION (Microbial infection) Acts as a receptor for the Dengue virus.FUNCTION (Microbial infection) Acts as a receptor for the Sindbis virus.FUNCTION (Microbial infection) Acts as a receptor for the Venezuelan equine encephalitis virus.FUNCTION (Microbial infection) Acts as a receptor for the pathogenic prion protein.FUNCTION (Microbial infection) Acts as a receptor for bacteria.SUBUNIT Monomer (37LRP) and homodimer (67LR). Component of the small ribosomal subunit. Mature ribosomes consist of a small (40S) and a large (60S) subunit. The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S). Interacts with RPS21. Interacts with several laminins including at least LAMB1. Interacts with MDK (By similarity). The mature dimeric form interacts with PPP1R16B (via its fourth ankyrin repeat). Interacts with PPP1CA only in the presence of PPP1R16B.SUBUNIT (Microbial infection) 67LR interacts with capsid protein of Adeno-associated virus 2,3,8 and 9.SUBUNIT (Microbial infection) 67LR interacts with envelope protein of dengue virus.SUBUNIT (Microbial infection) 6s7LR interacts with E2 glycoprotein of Sindbis and Venezuelan equine encephalitis virus (PubMed:8764073, PubMed:1385835).PTM Acylated. Acylation may be a prerequisite for conversion of the monomeric 37 kDa laminin receptor precursor (37LRP) to the mature dimeric 67 kDa laminin receptor (67LR), and may provide a mechanism for membrane association (PubMed:9581863).PTM Cleaved by stromelysin-3 (ST3) at the cell surface. Cleavage by stromelysin-3 may be a mechanism to alter cell-extracellular matrix interactions.MISCELLANEOUS This protein appears to have acquired a second function as a laminin receptor specifically in the vertebrate lineage.MISCELLANEOUS It is thought that in vertebrates 37/67 kDa laminin receptor acquired a dual function during evolution. It developed from the ribosomal protein SA, playing an essential role in the protein biosynthesis lacking any laminin binding activity, to a cell surface receptor with laminin binding activity.SIMILARITY Belongs to the universal ribosomal protein uS2 family.

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Reactome DB_ID: 72345

UniProt:P62244 RPS15A

RPS15A

RPS15AOK/SW-cl.82FUNCTION Structural component of the ribosome (PubMed:23636399). Required for proper erythropoiesis (PubMed:27909223).SUBUNIT Component of the 40S ribosomal subunit.SIMILARITY Belongs to the universal ribosomal protein uS8 family.

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Reactome DB_ID: 72381

UniProt:P62753 RPS6

RPS6

OK/SW-cl.2RPS6FUNCTION May play an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA.PTM Ribosomal protein S6 is the major substrate of protein kinases in eukaryote ribosomes. The phosphorylation is stimulated by growth factors, tumor promoting agents, and mitogens. It is dephosphorylated at growth arrest. Phosphorylated at Ser-235 and Ser-236 by RPS6KA1 and RPS6KA3; phosphorylation at these sites facilitates the assembly of the preinitiation complex.PTM Specifically hydroxylated (with R stereochemistry) at C-3 of Arg-137 by KDM8.SIMILARITY Belongs to the eukaryotic ribosomal protein eS6 family.

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249

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Reactome DB_ID: 72379

UniProt:P46782 RPS5

RPS5

RPS5SIMILARITY Belongs to the universal ribosomal protein uS7 family.

UniProtP46782

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204

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Reactome DB_ID: 72341

UniProt:P62269 RPS18

RPS18

RPS18D6S218EFUNCTION Located at the top of the head of the 40S subunit, it contacts several helices of the 18S rRNA.SIMILARITY Belongs to the universal ribosomal protein uS13 family.

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152

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Reactome DB_ID: 72327

UniProt:P62280 RPS11

RPS11

RPS11PTM Citrullinated by PADI4.SIMILARITY Belongs to the universal ribosomal protein uS17 family.

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158

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Reactome DB_ID: 72343

UniProt:P39019 RPS19

RPS19

RPS19FUNCTION Required for pre-rRNA processing and maturation of 40S ribosomal subunits.SUBUNIT Interacts with RPS19BP1.TISSUE SPECIFICITY Higher level expression is seen in the colon carcinoma tissue than normal colon tissue.SIMILARITY Belongs to the eukaryotic ribosomal protein eS19 family.

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Reactome DB_ID: 72385

UniProt:P62241 RPS8

RPS8

RPS8OK/SW-cl.83SUBUNIT Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs.SIMILARITY Belongs to the eukaryotic ribosomal protein eS8 family.

UniProtP62241

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208

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Reactome DB_ID: 72357

UniProt:P62851 RPS25

RPS25

RPS25SIMILARITY Belongs to the eukaryotic ribosomal protein eS25 family.

UniProtP62851

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125

EQUAL

Reactome DB_ID: 72335

UniProt:P62841 RPS15

RPS15

RPS15RIGSIMILARITY Belongs to the universal ribosomal protein uS19 family.

UniProtP62841

EQUAL

145

EQUAL

Reactome DB_ID: 72363

UniProt:P62979 RPS27A

RPS27A

UBA80RPS27AUBCEP1SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family.

EQUAL

156

EQUAL

Reactome DB_ID: 72365

UniProt:P62857 RPS28

RPS28

RPS28SUBUNIT Component of the 40S small ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eS28 family.

UniProtP62857

EQUAL

Reactome DB_ID: 72391

EMBL:X03205 18S rRNA18S rRNA

EMBLX03205

Reactome DB_ID: 72329

UniProt:P25398 RPS12

RPS12

RPS12SIMILARITY Belongs to the eukaryotic ribosomal protein eS12 family.

UniProtP25398

EQUAL

132

EQUAL

Reactome DB_ID: 72373

UniProt:P61247 RPS3A

RPS3A

MFTLRPS3AFTE1FUNCTION May play a role during erythropoiesis through regulation of transcription factor DDIT3.SUBUNIT Component of the small ribosomal subunit. Mature ribosomes consist of a small (40S) and a large (60S) subunit. The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Binds with high affinity to IPO4. Interacts with DDIT3.SIMILARITY Belongs to the eukaryotic ribosomal protein eS1 family.

UniProtP61247

EQUAL

264

EQUAL

Reactome DB_ID: 72333

UniProt:P62263 RPS14

RPS14

RPS14PRO2640SIMILARITY Belongs to the universal ribosomal protein uS11 family.

UniProtP62263

EQUAL

151

EQUAL

Reactome DB_ID: 72371

UniProt:P62861 FAU

FAU

FAUMISCELLANEOUS This ribosomal protein is synthesized as a C-terminal extension protein (CEP) of a ubiquitin-like protein.SIMILARITY Belongs to the eukaryotic ribosomal protein eS30 family.

UniProtP62861

EQUAL

Reactome DB_ID: 72353

UniProt:P62266 RPS23

RPS23

RPS23FUNCTION Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:28257692, PubMed:23636399, PubMed:25957688, PubMed:25901680). The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel (PubMed:23636399, PubMed:25957688, PubMed:25901680). Plays an important role in translational accuracy (PubMed:28257692).SUBUNIT Component of the 40S small ribosomal subunit.PTM Hydroxylation at Pro-62 affects translation termination efficiency.SIMILARITY Belongs to the universal ribosomal protein uS12 family.

UniProtP62266

EQUAL

143

EQUAL

Reactome DB_ID: 72337

UniProt:P62249 RPS16

RPS16

RPS16SIMILARITY Belongs to the universal ribosomal protein uS9 family.

UniProtP62249

EQUAL

146

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868839

RPS27,RPS27L [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS27 [cytosol]

UniProtP42677

Reactome DB_ID: 72351

UniProt:P63220 RPS21

RPS21

RPS21SUBUNIT Component of the 40S small ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eS21 family.

UniProtP63220

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868832

RPS4X,RPS4Y1,RPS4Y2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS4X [cytosol]RPS4Y1 [cytosol]

UniProtP62701UniProtP22090

Reactome DB_ID: 72347

UniProt:P15880 RPS2

RPS2

RPS4RPS2PTM Citrullinated by PADI4 in the Arg/Gly-rich region.PTM Asymmetric arginine dimethylation by PRMT3 occurs at multiple sites in the Arg/Gly-rich region.SIMILARITY Belongs to the universal ribosomal protein uS5 family.

UniProtP15880

EQUAL

293

EQUAL

Reactome DB_ID: 72355

UniProt:P62847 RPS24

RPS24

RPS24FUNCTION Required for processing of pre-rRNA and maturation of 40S ribosomal subunits.TISSUE SPECIFICITY Mature tissues, such as adult brain, skeletal muscle, heart, and kidney, express low levels, whereas tissues and organs with significant populations of proliferating cells, such as fetal brain, placenta, bone marrow, and various glandular organs, contain significantly higher levels.SIMILARITY Belongs to the eukaryotic ribosomal protein eS24 family.

UniProtP62847

EQUAL

133

EQUAL

Reactome Database ID Release 7572392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=72392ReactomeR-HSA-72392

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-72392.2

Reactome DB_ID: 72499

60S ribosomal complex [cytosol]

60S ribosomal complex

Reactome DB_ID: 72474

UniProt:P36578 RPL4

RPL4

RPL4RPL1SUBUNIT May bind IPO9 with low affinity. Interacts with RBM3 (By similarity).PTM Citrullinated by PADI4.SIMILARITY Belongs to the universal ribosomal protein uL4 family.

UniProtP36578

EQUAL

427

EQUAL

Reactome DB_ID: 72416

UniProt:P61313 RPL15

RPL15

TCBAP0781RPL15EC45SUBUNIT Interacts with IFIT1 (via TPR repeats 1-4).SIMILARITY Belongs to the eukaryotic ribosomal protein eL15 family.

UniProtP61313

EQUAL

204

EQUAL

Reactome DB_ID: 72458

UniProt:P49207 RPL34

RPL34

RPL34FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL34 family.

UniProtP49207

EQUAL

117

EQUAL

Reactome DB_ID: 72498

EMBL:M11167 28S rRNA28S rRNA

EMBLM11167

EQUAL

5025

EQUAL

Reactome DB_ID: 72412

UniProt:P40429 RPL13A

RPL13A

RPL13AFUNCTION Associated with ribosomes but is not required for canonical ribosome function and has extra-ribosomal functions. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the ribosome and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation. In the GAIT complex interacts with m7G cap-bound eIF4G at or near the eIF3-binding site and blocks the recruitment of the 43S ribosomal complex. Involved in methylation of rRNA.SUBUNIT Component of the 60S ribosome. Component of the GAIT complex. Interacts with EIF4G1.PTM Phosphorylation at Ser-77 upon interferon-gamma treatment in monocytes involves a DAPK1-DAPK3 kinase cascade and is causing release from the ribosome, association with the GAIT complex and subsequent involvement in transcript-selective translation inhibition.PTM Citrullinated by PADI4.SIMILARITY Belongs to the universal ribosomal protein uL13 family.

UniProtP40429

EQUAL

203

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868854

RPL10,RPL10L [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL10 [cytosol]

UniProtP27635

Reactome DB_ID: 72398

UniProt:P05386 RPLP1

RPLP1

RPLP1RRP1FUNCTION Plays an important role in the elongation step of protein synthesis.SUBUNIT Heterodimer with RPLP2 at the lateral ribosomal stalk of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein P1/P2 family.

UniProtP05386

EQUAL

114

EQUAL

Reactome DB_ID: 72444

UniProt:P46779 RPL28

RPL28

RPL28FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL28 family.

UniProtP46779

EQUAL

137

EQUAL

Reactome DB_ID: 72430

UniProt:P62829 RPL23

RPL23

RPL23SIMILARITY Belongs to the universal ribosomal protein uL14 family.

UniProtP62829

EQUAL

140

EQUAL

Reactome DB_ID: 72396

UniProt:P05388 RPLP0

RPLP0

RPLP0FUNCTION Ribosomal protein P0 is the functional equivalent of E.coli protein L10.SUBUNIT P0 forms a pentameric complex by interaction with dimers of P1 and P2 (PubMed:3323886). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Interacts with APEX1 (PubMed:19188445). Interacts with FMR1 isoform 6 (PubMed:24658146).SIMILARITY Belongs to the universal ribosomal protein uL10 family.

UniProtP05388

EQUAL

317

EQUAL

Reactome DB_ID: 72478

UniProt:P62945 RPL41

RPL41

RPL41FUNCTION Interacts with the beta subunit of protein kinase CKII and stimulates phosphorylation of DNA topoisomerase II alpha by CKII.SIMILARITY Belongs to the eukaryotic ribosomal protein eL41 family.CAUTION There are multiple pseudogenes of this gene dispersed through the genome.

UniProtP62945

EQUAL

Reactome DB_ID: 72464

UniProt:Q9Y3U8 RPL36

RPL36

RPL36FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL36 family.

UniProtQ9Y3U8

EQUAL

105

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868827

RPL26,RPL26L1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL26 [cytosol]

UniProtP61254

Reactome DB_ID: 72440

UniProt:P61353 RPL27

RPL27

RPL27FUNCTION Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680). Required for proper rRNA processing and maturation of 28S and 5.8S rRNAs (PubMed:25424902).SUBUNIT Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680). Interacts with RRP1B (PubMed:20926688). Interacts with DHX33 (PubMed:26100019).SIMILARITY Belongs to the eukaryotic ribosomal protein eL27 family.

UniProtP61353

EQUAL

136

EQUAL

Reactome DB_ID: 72432

UniProt:P62750 RPL23A

RPL23A

RPL23AFUNCTION Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Binds a specific region on the 26S rRNA. May promote p53/TP53 degradation possibly through the stimulation of MDM2-mediated TP53 polyubiquitination (PubMed:26203195).SUBUNIT Interacts with LYAR and GNL2 (PubMed:26203195). Interacts with MDM2; this interaction may promote MDM2-mediated p53/TP53 polyubiquitination (PubMed:26203195).INDUCTION May be down-regulated by GNL2 (at protein level).PTM N-terminus is methylated by METTL11A/NTM1.PTM Citrullinated by PADI4.SIMILARITY Belongs to the universal ribosomal protein uL23 family.

UniProtP62750

EQUAL

156

EQUAL

Reactome DB_ID: 72442

UniProt:P46776 RPL27A

RPL27A

RPL27APTM Hydroxylated on His-39 by MINA.SIMILARITY Belongs to the universal ribosomal protein uL15 family.

UniProtP46776

EQUAL

148

EQUAL

Reactome DB_ID: 72418

UniProt:P18621 RPL17

RPL17

RPL17FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.TISSUE SPECIFICITY Expressed in pancreas, lung, colon, cystic duct, gall bladder, kidney and liver. Expressed at high levels in the well differentiated pancreatic tumor cell lines HPAF, COLO 357 and Capan-1, the moderately differentiated pancreatic tumor cell lines T3M-4, AsPc-1 and BxPc-3, the poorly differentiated pancreatic tumor cell line MIA PaCa-2, and the pancreatic tumor cell lines of undefined differentiation status such as SW979. Expressed at lower levels in the poorly differentiated pancreatic tumor cell lines HCG-25 and PANC-1.SIMILARITY Belongs to the universal ribosomal protein uL22 family.

UniProtP18621

EQUAL

184

EQUAL

Reactome DB_ID: 72492

UniProt:P32969 RPL9

RPL9

OK/SW-cl.103RPL9P7RPL9P8RPL9P9RPL9SIMILARITY Belongs to the universal ribosomal protein uL6 family.

UniProtP32969

EQUAL

192

EQUAL

Reactome DB_ID: 72424

UniProt:P84098 RPL19

RPL19

RPL19PTM Citrullinated by PADI4.SIMILARITY Belongs to the eukaryotic ribosomal protein eL19 family.

UniProtP84098

EQUAL

196

EQUAL

Reactome DB_ID: 72452

UniProt:P62888 RPL30

RPL30

RPL30SIMILARITY Belongs to the eukaryotic ribosomal protein eL30 family.

UniProtP62888

EQUAL

115

EQUAL

Reactome DB_ID: 72426

UniProt:P46778 RPL21

RPL21

RPL21FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL21 family.

UniProtP46778

EQUAL

160

EQUAL

Reactome DB_ID: 72490

UniProt:P62917 RPL8

RPL8

RPL8FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit (Probable). Interacts with CRY1 (By similarity).PTM Hydroxylated on His-216 by RIOX1. The modification is impaired by hypoxia.MISCELLANEOUS This protein can be partially incorporated into E.coli polysomes in vivo, indicating it can replace the endogenous protein.SIMILARITY Belongs to the universal ribosomal protein uL2 family.

UniProtP62917

EQUAL

257

EQUAL

Reactome DB_ID: 72494

EMBL:V00589 5S rRNA5S rRNA

EMBLV00589

Reactome DB_ID: 72414

UniProt:P50914 RPL14

RPL14

RPL14FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.POLYMORPHISM The poly-Ala stretch is highly polymorphic.SIMILARITY Belongs to the eukaryotic ribosomal protein eL14 family.

UniProtP50914

EQUAL

215

EQUAL

Reactome DB_ID: 72408

UniProt:P30050 RPL12

RPL12

RPL12FUNCTION Binds directly to 26S ribosomal RNA.SIMILARITY Belongs to the universal ribosomal protein uL11 family.

UniProtP30050

EQUAL

165

EQUAL

Reactome DB_ID: 72486

UniProt:P18124 RPL7

RPL7

RPL7FUNCTION Component of the large ribosomal subunit (PubMed:12962325). Binds to G-rich structures in 28S rRNA and in mRNAs. Plays a regulatory role in the translation apparatus; inhibits cell-free translation of mRNAs.SUBUNIT Component of the large ribosomal subunit (Probable). Homodimer. Interacts with DHX33 (PubMed:26100019).SIMILARITY Belongs to the universal ribosomal protein uL30 family.

UniProtP18124

EQUAL

248

EQUAL

Reactome DB_ID: 72406

UniProt:P62913 RPL11

RPL11

RPL11FUNCTION Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs (PubMed:19061985, PubMed:12962325, PubMed:24120868). It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53 (PubMed:24120868). Promotes nucleolar location of PML (By similarity).SUBUNIT Component of the large ribosomal subunit (LSU). Part of a LSU subcomplex, the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11 (PubMed:24120868). Interacts with PML (By similarity). Interacts with MDM2; negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:24120868). Interacts with NOP53; retains RPL11 into the nucleolus (PubMed:24556985, PubMed:27829214).SIMILARITY Belongs to the universal ribosomal protein uL5 family.

UniProtP62913

EQUAL

178

EQUAL

Reactome DB_ID: 72484

UniProt:Q02878 RPL6

RPL6

TXREB1RPL6FUNCTION Component of the large ribosomal subunit.FUNCTION (Microbial infection) Specifically binds to domain C of the Tax-responsive enhancer element in the long terminal repeat of HTLV-I (PubMed:8457378).SUBUNIT Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25957688, PubMed:25901680). May bind IPO9 with low affinity (By similarity).SIMILARITY Belongs to the eukaryotic ribosomal protein eL6 family.

UniProtQ02878

EQUAL

288

EQUAL

Reactome DB_ID: 72482

UniProt:P46777 RPL5

RPL5

RPL5MSTP030FUNCTION Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs (PubMed:12962325, PubMed:19061985, PubMed:24120868, PubMed:23636399). It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53 (PubMed:24120868).SUBUNIT Component of the large ribosomal subunit (LSU). Part of a LSU subcomplex, the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11 (PubMed:24120868). Interacts with isoform 1 of NVL in an ATP-dependent manner (PubMed:15469983). Interacts with RRP1B (PubMed:20926688).SIMILARITY Belongs to the universal ribosomal protein uL18 family.

UniProtP46777

EQUAL

297

EQUAL

Reactome DB_ID: 72400

UniProt:P05387 RPLP2

RPLP2

D11S2243ERPP2RPLP2FUNCTION Plays an important role in the elongation step of protein synthesis.SUBUNIT Heterodimer with RPLP1 at the lateral ribosomal stalk of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein P1/P2 family.

UniProtP05387

EQUAL

115

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868851

RPL3,RPL3L [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL3 [cytosol]

UniProtP39023

Reactome DB_ID: 72456

UniProt:P62910 RPL32

RPL32

RPL32PP9932SIMILARITY Belongs to the eukaryotic ribosomal protein eL32 family.

UniProtP62910

EQUAL

135

EQUAL

Reactome DB_ID: 72460

UniProt:P42766 RPL35

RPL35

RPL35FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the universal ribosomal protein uL29 family.

UniProtP42766

EQUAL

123

EQUAL

Reactome DB_ID: 72476

UniProt:P62987 UBA52

UBA52

UBCEP2UBA52SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family.

EQUAL

128

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868819

RPL36A,RPL36AL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL36A [cytosol]

UniProtP83881

Reactome DB_ID: 72434

UniProt:P83731 RPL24

RPL24

RPL24SIMILARITY Belongs to the eukaryotic ribosomal protein eL24 family.

UniProtP83731

EQUAL

157

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8868847

RPL22,RPL22L1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL22 [cytosol]

UniProtP35268

Reactome DB_ID: 72462

UniProt:P18077 RPL35A

RPL35A

RPL35AGIG33FUNCTION Required for the proliferation and viability of hematopoietic cells. Plays a role in 60S ribosomal subunit formation. The protein was found to bind to both initiator and elongator tRNAs and consequently was assigned to the P site or P and A site.MISCELLANEOUS Knockdown of RPL35A in hematopoietic cell lines results in decreased cell proliferation, increased apoptosis, decreased biogenesis of mature 60S ribosomal subunit, and abnormal processing of large ribosomal subunit rRNA.SIMILARITY Belongs to the eukaryotic ribosomal protein eL33 family.

UniProtP18077

EQUAL

110

EQUAL

Reactome DB_ID: 72470

UniProt:P63173 RPL38

RPL38

RPL38SIMILARITY Belongs to the eukaryotic ribosomal protein eL38 family.

UniProtP63173

EQUAL

Reactome DB_ID: 72466

UniProt:P61927 RPL37

RPL37

RPL37FUNCTION Binds to the 23S rRNA.SIMILARITY Belongs to the eukaryotic ribosomal protein eL37 family.

UniProtP61927

EQUAL

Reactome DB_ID: 72410

UniProt:P26373 RPL13

RPL13

BBC1OK/SW-cl.46RPL13FUNCTION Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:31630789, PubMed:23636399). The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules (Probable). The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain (Probable). The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel (Probable). As part of the LSU, it is probably required for its formation and the maturation of rRNAs (PubMed:31630789). Plays a role in bone development (PubMed:31630789).SUBUNIT Component of the 60S large ribosomal subunit (LSU).TISSUE SPECIFICITY Higher levels of expression in benign breast lesions than in carcinomas.SIMILARITY Belongs to the eukaryotic ribosomal protein eL13 family.

UniProtP26373

EQUAL

211

EQUAL

Reactome DB_ID: 72422

UniProt:Q02543 RPL18A

RPL18A

RPL18ASUBUNIT Binds IPO9 with high affinity.SIMILARITY Belongs to the eukaryotic ribosomal protein eL20 family.

UniProtQ02543

EQUAL

176

EQUAL

Reactome DB_ID: 72404

UniProt:P62906 RPL10A

RPL10A

NEDD6RPL10AFUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the universal ribosomal protein uL1 family.

UniProtP62906

EQUAL

217

EQUAL

Reactome DB_ID: 72496

EMBL:J01866 5.8S rRNA5.8S rRNA

EMBLJ01866Converted from EntitySet in Reactome

Reactome DB_ID: 8868812

RPL39,RPL39L [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPL39 [cytosol]

UniProtP62891

Reactome DB_ID: 72420

UniProt:Q07020 RPL18

RPL18

RPL18FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL18 family.

UniProtQ07020

EQUAL

188

EQUAL

Reactome DB_ID: 72488

UniProt:P62424 RPL7A

RPL7A

RPL7ASURF3SURF-3SUBUNIT Interacts with CRY1 (By similarity). Interacts with DICER1, AGO2, TARBP2, MOV10 and EIF6; they form a large RNA-induced silencing complex (RISC) (PubMed:17507929).DISEASE Chromosomal recombination involving RPL7A activates the receptor kinase domain of the TRK oncogene.SIMILARITY Belongs to the eukaryotic ribosomal protein eL8 family.

UniProtP62424

EQUAL

266

EQUAL

Reactome DB_ID: 72468

UniProt:P61513 RPL37A

RPL37A

RPL37ASIMILARITY Belongs to the eukaryotic ribosomal protein eL43 family.

UniProtP61513

EQUAL

Reactome DB_ID: 72446

UniProt:P47914 RPL29

RPL29

RPL29FUNCTION Component of the large ribosomal subunit.SUBUNIT Component of the large ribosomal subunit.SIMILARITY Belongs to the eukaryotic ribosomal protein eL29 family.

UniProtP47914

EQUAL

159

EQUAL

Reactome DB_ID: 72454

UniProt:P62899 RPL31

RPL31

RPL31SIMILARITY Belongs to the eukaryotic ribosomal protein eL31 family.

UniProtP62899

EQUAL

125

EQUAL

Reactome Database ID Release 7572499Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=72499ReactomeR-HSA-72499

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-72499.2Reactome Database ID Release 7572500Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=72500ReactomeR-HSA-72500

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-72500.1

Reactome DB_ID: 141679

tRNA [cytosol]

tRNA

transfer RNA

Reactome DB_ID: 72584

UniProt:Q04637 EIF4G1

EIF4G1

EIF4GIEIF4FEIF4GEIF4G1FUNCTION Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome. As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).SUBUNIT eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3. Interacts with eIF3, mutually exclusive with EIF4A1 or EIFA2, EIF4E and through its N-terminus with PAPBC1. Interacts through its C-terminus with the serine/threonine kinases MKNK1, and with MKNK2. Appears to act as a scaffold protein, holding these enzymes in place to phosphorylate EIF4E. Non-phosphorylated EIF4EBP1 competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. EIF4G1/EIF4G3 interacts with PABPC1 to bring about circularization of the mRNA. Rapamycin can attenuate insulin stimulation mediated by FKBPs. Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts with RBM4. Interacts with HNRNPD/AUF1; the interaction requires RNA. Directly interacts with EIF4G1 in an RNA-independent manner (PubMed:22872150).SUBUNIT (Microbial infection) Interacts with rotavirus A NSP3; in this interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of host protein synthesis.SUBUNIT (Microbial infection) Interacts with human adenovirus 5 protein 100K; this interaction promotes translational shunt in presence of polysomes containing viral tripartite leader mRNAs.PTM Phosphorylated at multiple sites in vivo. Phosphorylation at Ser-1185 by PRKCA induces binding to MKNK1.PTM Following infection by certain enteroviruses, rhinoviruses and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the leader protease in the case of aphthoviruses. This shuts down the capped cellular mRNA transcription.SIMILARITY Belongs to the eukaryotic initiation factor 4G family.

UniProtQ04637

EQUAL

1599

EQUAL

Reactome DB_ID: 9014609

Translated ROBO3.2 mRNA in complex with NMD-initiating UPF2 [cytosol]

Translated ROBO3.2 mRNA in complex with NMD-initiating UPF2

Reactome DB_ID: 927798

Reactome DB_ID: 54433

EQUAL

437

EQUAL

Reactome DB_ID: 143378

Reactome DB_ID: 72500

Reactome DB_ID: 141679

Reactome DB_ID: 9014606

ROBO3.2 mRNA:CBC:EIF4G1:PABPC1 [cytosol]

ROBO3.2 mRNA:CBC:EIF4G1:PABPC1

Reactome DB_ID: 162460

Reactome DB_ID: 156803

EQUAL

636

EQUAL

Reactome DB_ID: 9014585

Reactome DB_ID: 72584

EQUAL

1599

EQUAL

Reactome Database ID Release 759014606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014606ReactomeR-HSA-9014606

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014606.1Reactome Database ID Release 759014609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014609ReactomeR-HSA-9014609

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014609.1Reactome Database ID Release 759014610Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014610ReactomeR-HSA-9014610

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014610.123746841Pubmed2013Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decayColak, DilekJi, Sheng-JianPorse, Bo TJaffrey, Samie RCell 153:1252-65

Translation of ROBO3.2 mRNA is negatively regulated by NMD

Based on studies in mice, translation of ROBO3.2 mRNA in commissural axons at the floor plate is negatively regulated by nonsense mediated decay (NMD). Deficiency of NMD components results in aberrant axonal trajectories after crossing the midline (Colak et al. 2013).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 9014585

Reactome DB_ID: 9014651

ROBO3.2 [plasma membrane]

ROBO3.2

Reactome Database ID Release 759014652Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014652ReactomeR-HSA-9014652

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014652.2

INHIBITION

Reactome Database ID Release 759014653Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014653ReactomeR-HSA-9014653

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014653.1

Reactome DB_ID: 9014609

Reactome Database ID Release 759010553Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010553ReactomeR-HSA-9010553

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010553.120071533Pubmed2010Dynamic expression of axon guidance cues required for optic tract development is controlled by fibroblast growth factor signalingAtkinson-Leadbeater, KarenBertolesi, Gabriel EHehr, Carrie LWebber, Christine ACechmanek, Paula BMcFarlane, SarahJ. Neurosci. 30:685-9319258013Pubmed2009Spatially distinct functions of PAX6 and NKX2.2 during gliogenesis in the ventral spinal cordGenethliou, NicholasPanayiotou, ElenaPanayi, HelenOrford, MichaelMean, RichardLapathitis, GeorgeMalas, StavrosBiochem. Biophys. Res. Commun. 382:69-73

3.4

Proteolytic processing of SLIT

The full length SLIT proteins are secreted and, when not bound to ROBO receptors, are indirectly associated with the plasma membrane via the extracellular matrix proteins. These full length SLITs undergo posttranslational modification and proteolytic processing to generate an N-terminal fragment (SLIT2-N) and a corresponding C-terminal fragment (SLIT2-C). SLIT2 is cleaved within the EGF repeats, between EGF5 and EGF6, by unknown proteases. Cleavage of SLIT proteins is evolutionarily conserved, although the molecular biological significance is unknown. The N-terminal fragment of SLIT2 stimulates growth and branching of dorsal root ganglia (DRG) axons, and this activity is opposed by un-cleaved SLIT. The stimulation of axon branching is mediated by ROBO receptors. Additional functional differences between the full-length and N-terminal forms have been discovered in their abilities to repel different populations of axons and dendrites. Finally, SLIT can attract migrating muscles in the fly, and also human endothelial cells, both via ROBO receptors (Brose et al. 1999, Wang et al. 1999).SLIT C-terminal fragments may transduce signaling independently of ROBO receptors and Neuropilins (semaphorin receptors) by directly binding to Plexin A1 (Delloye-Bourgeois et al. 2015).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 426409

EQUAL

1121

EQUAL

Reactome DB_ID: 426412

1122

EQUAL

1529

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 428470

Unidentified protease [cytosol]

Unidentified protease

GO0008233

GO molecular function

Reactome Database ID Release 75428539Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428539Reactome Database ID Release 75376149Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376149ReactomeR-HSA-376149

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376149.310102268Pubmed1999Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidanceBrose, KBland, KSWang, KHArnott, DHenzel, WGoodman, CSTessier-Lavigne, MKidd, ThomasCell 96:795-80625485759Pubmed2015PlexinA1 is a new Slit receptor and mediates axon guidance function of Slit C-terminal fragmentsDelloye-Bourgeois, CélineJacquier, ArnaudCharoy, CamilleReynaud, FlorieNawabi, HomairaThoinet, KarineKindbeiter, KarineYoshida, YutakaZagar, YvrickKong, YouxinJones, Yvonne EFalk, JulienChédotal, AlainCastellani, ValérieNat. Neurosci. 18:36-4510102266Pubmed1999Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branchingWang, KHBrose, KArnott, DKidd, ThomasGoodman, CSHenzel, WTessier-Lavigne, MCell 96:771-84

Glypican-1 (GPC1) binds SLIT2

SLIT2 and both its natural cleavage products bind glypican-1 (GPC1), a glycosyl phosphatidyl inositol (GPI) anchored heparan sulfate proteoglycan (HSPG), through its C-terminus. Besides glypican-1, other HSPG may also be involved in SLIT2 binding. GPC1:HSPG is important for high affinity binding of SLIT to its receptor and for the repulsive activity of SLIT. SLIT-ROBO signaling strictly requires binding to heparan sulfate. HSPGs may also modulate the extracellular distribution or stability of SLIT proteins (Ronca et al. 2001, Zhang et al. 2004).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23

Converted from EntitySet in Reactome

Reactome DB_ID: 9014805

SLIT2,SLIT2 cleavage fragments [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySLIT2 [extracellular region]SLIT2(31-1121) [extracellular region]SLIT2(1122-1529) [extracellular region]

Reactome DB_ID: 428493

GPC1:HSPG [plasma membrane]

GPC1:HSPG

Glypican-1:HSPG

Reactome DB_ID: 425952

UniProt:P35052 GPC1

GPC1

GPC1FUNCTION Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.PTM S-nitrosylated in a Cu(2+)-dependent manner. Nitric acid (NO) is released from the nitrosylated cysteines by ascorbate or by some other reducing agent, in a Cu(2+) or Zn(2+) dependent manner. This free nitric oxide is then capable of cleaving the heparan sulfate side chains.PTM N- and O-glycosylated. N-glycosylation is mainly of the complex type containing sialic acid. O-glycosylated with heparan sulfate. The heparan sulfate chains can be cleaved either by the action of heparanase or, degraded by a deaminative process that uses nitric oxide (NO) released from the S-nitrosylated cysteines. This process is triggered by ascorbate, or by some other reducing agent, in a Cu(2+)- or Zn(2+) dependent manner. Cu(2+) ions are provided by ceruloproteins such as APP, PRNP or CP which associate with GCP1 in intracellular compartments or lipid rafts.PTM This cell-associated glypican is further processed to give rise to a medium-released species.DISEASE Associates (via the heparan sulfate side chains) with fibrillar APP amyloid-beta peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain (PubMed:15084524).DISEASE Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains (PubMed:16645004).SIMILARITY Belongs to the glypican family.

UniProtP35052

EQUAL

530

EQUAL

Reactome DB_ID: 381898

heparan sulfate N-acetyl-alpha-D-glucosaminide [ChEBI:17421]

heparan sulfate N-acetyl-alpha-D-glucosaminide

ChEBI17421Reactome Database ID Release 75428493Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428493ReactomeR-HSA-428493

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428493.2

Reactome DB_ID: 428489

SLIT2,SLIT2 cleavage fragments:GPC1:HSPG [plasma membrane]

SLIT2,SLIT2 cleavage fragments:GPC1:HSPG

Slit2:Glypican-1

Converted from EntitySet in Reactome

Reactome DB_ID: 9014805

Reactome DB_ID: 428493

Reactome Database ID Release 75428489Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428489ReactomeR-HSA-428489

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428489.4Reactome Database ID Release 75428518Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428518ReactomeR-HSA-428518

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428518.415063764Pubmed2004Structural determinants of heparan sulfate interactions with Slit proteinsZhang, FRonca, FLinhardt, RJMargolis, RUBiochem Biophys Res Commun 317:352-711375980Pubmed2001Characterization of Slit protein interactions with glypican-1Ronca, FAndersen, JSPaech, VMargolis, RUJ Biol Chem 276:29141-7

SLITs bind keratan sulfate

SLIT2 is expressed by corneal epithelial cells and able to bind to keratan sulfate, which is part of the corneal stroma extracellular matrix. This interaction may influence corneal nerve growth cone penetration. SLIT3 may also interact with keratan sulfate, as well as ROBO receptors ROBO1 and ROBO2 (Conrad et al. 2010).

Authored: Orlic-Milacic, Marija, 2017-06-23Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-08-04

Reactome DB_ID: 2299699

keratan sulfate [ChEBI:60924]

keratan sulfate

keratosulfatekeratan sulfates

ChEBI60924Converted from EntitySet in Reactome

Reactome DB_ID: 9010822

SLIT2,(SLIT3) [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySLIT2 [extracellular region]

Reactome DB_ID: 9010818

SLIT2,(SLIT3):Keratan sulfate [extracellular region]

SLIT2,(SLIT3):Keratan sulfate

Reactome DB_ID: 2299699

Converted from EntitySet in Reactome

Reactome DB_ID: 9010822

Reactome Database ID Release 759010818Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010818ReactomeR-HSA-9010818

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010818.2Reactome Database ID Release 759010815Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010815ReactomeR-HSA-9010815

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010815.120375348Pubmed2010Proteomic analysis of potential keratan sulfate, chondroitin sulfate A, and hyaluronic acid molecular interactionsConrad, Abigail HZhang, YuntaoTasheva, Elena SConrad, Gary WInvest. Ophthalmol. Vis. Sci. 51:4500-15

ROBOs bind keratan sulfate

ROBO receptors ROBO1 and ROBO2 interact with keratan sulfate through their extracellular regions (Conrad et al. 2010).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 2299699

Converted from EntitySet in Reactome

Reactome DB_ID: 428477

ROBO1,ROBO2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityROBO2 [plasma membrane]ROBO1 [plasma membrane]

Reactome DB_ID: 9014813

ROBO1,ROBO2:Keratan sulfate [plasma membrane]

ROBO1,ROBO2:Keratan sulfate

Reactome DB_ID: 2299699

Converted from EntitySet in Reactome

Reactome DB_ID: 428477

Reactome Database ID Release 759014813Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014813ReactomeR-HSA-9014813

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014813.1Reactome Database ID Release 759014812Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014812ReactomeR-HSA-9014812

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014812.1

ROBO1 binds SLIT2

SLIT2 ligand forms a complex with the ROBO1 receptor (Brose et al. 1999). The SLIT family consists of three members that are all expressed in the ventral midline (floor plate) of the neural tube. SLIT1 is predominantly expressed in the nervous system whereas SLIT2 and SLIT3 are also expressed outside the nervous system. SLIT proteins are the ligands for the ROBO receptors. In humans, there are four ROBO genes: ROBO1, ROBO2, ROBO3 and ROBO4. The extracellular domain of ROBO comprises five Ig domains and three FN domains except for ROBO4 (two Ig + two FN). Ig1 and Ig2 domains of ROBO1 and ROBO2 are highly conserved and are important for SLIT binding. The concave face of SLIT's second LRR domain accommodates the Ig1 and Ig2 domains of ROBO1 and ROBO2. ROBO3 does not bind SLITs (Camurri et al. 2005, Mambetisaeva et al. 2005, Zelina et al. 2014, Jaworski et al. 2015). SLIT binding with ROBO4 is controversial as the interaction is weak and it has been observed using the in-vitro methods (Wang et al. 1999, Brose et al. 1999, Piper et al. 2003, Andrews et al. 2007). Binding of secreted (cleaved) SLIT2 to ROBO1 and ROBO2 is involved in fasciculation (bundling) of motor axons, which facilitates axon pathfinding and muscle innervation (Jaworski and Tessier-Lavigne 2012).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 204361

EQUAL

1651

EQUAL

Reactome DB_ID: 390371

ROBO1:SLIT2 [plasma membrane]

ROBO1:SLIT2

Robo1:Slit2:Glypican-1

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 204361

EQUAL

1651

EQUAL

Reactome Database ID Release 75390371Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390371ReactomeR-HSA-390371

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390371.4Reactome Database ID Release 75204364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=204364ReactomeR-HSA-204364

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-204364.326586761Pubmed2015Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2Jaworski, AlexanderTom, IreneTong, Raymond KGildea, Holly KKoch, Alexander WGonzalez, Lino CTessier-Lavigne, MarcScience 350:961-525433640Pubmed2014Signaling switch of the axon guidance receptor Robo3 during vertebrate evolutionZelina, PavolBlockus, HeikeZagar, YvrickPéres, AmélieFriocourt, FrançoisWu, ZhuhaoRama, NicolasFouquet, CoralieHohenester, ErhardTessier-Lavigne, MarcSchweitzer, JörnRoest Crollius, HuguesChédotal, AlainNeuron 84:1258-7216226035Pubmed2005Evidence for the existence of two Robo3 isoforms with divergent biochemical propertiesCamurri, LauraMambetisaeva, ElviraDavies, DParnavelas, JohnSundaresan, VasiAndrews, WilliamMol. Cell. Neurosci. 30:485-9322306607Pubmed2012Autocrine/juxtaparacrine regulation of axon fasciculation by Slit-Robo signalingJaworski, AlexanderTessier-Lavigne, MarcNat. Neurosci. 15:367-917553100Pubmed2007Slit-Robo interactions during cortical developmentAndrews, WDBarber, MParnavelas, JGJ Anat 211:188-9815768400Pubmed2005Robo family of proteins exhibit differential expression in mouse spinal cord and Robo-Slit interaction is required for midline crossing in vertebrate spinal cordMambetisaeva, Elvira TAndrews, WilliamCamurri, LauraAnnan, AdelaideSundaresan, VasiDev. Dyn. 233:41-5112508280Pubmed2003Movement through Slits: cellular migration via the Slit familyPiper, MatthewLittle, MBioessays 25:32-8

ROBO2 binds SLIT2

ROBO2 receptor binds to SLIT2 ligand (Brose et al. 1999, Nguyen Ba-Charvet et al. 2001).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 197747

EQUAL

1378

EQUAL

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 9010899

ROBO2:SLIT2 [plasma membrane]

ROBO2:SLIT2

Reactome DB_ID: 197747

EQUAL

1378

EQUAL

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome Database ID Release 759010899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010899ReactomeR-HSA-9010899

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010899.2Reactome Database ID Release 759010898Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010898ReactomeR-HSA-9010898

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010898.211404413Pubmed2001Diversity and specificity of actions of Slit2 proteolytic fragments in axon guidanceNguyen Ba-Charvet, K TBrose, KMa, LWang, K HMarillat, VSotelo, CTessier-Lavigne, MChédotal, AJ. Neurosci. 21:4281-9

ROBO1,ROBO2 bind SLIT3

Based on studies in mice, SLIT3 can bind to both ROBO1 and ROBO2 receptors (Mommersteeg et al. 2013). The interaction between SLIT3 and ROBO2 contributes to targeting of axons of olfactory sensory neurons (Cho et al. 2012).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Converted from EntitySet in Reactome

Reactome DB_ID: 428477

Reactome DB_ID: 204357

UniProt:O75094 SLIT3

SLIT3

MEGF5SLIL2UNQ691/PRO1336SLIT3KIAA0814FUNCTION May act as molecular guidance cue in cellular migration, and function may be mediated by interaction with roundabout homolog receptors.TISSUE SPECIFICITY Predominantly expressed in thyroid.

UniProtO75094

EQUAL

1523

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 9014835

SLIT3:ROBO1,ROBO2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 759014834Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014834ReactomeR-HSA-9014834

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014834.223255421Pubmed2013Slit-roundabout signaling regulates the development of the cardiac systemic venous return and pericardiumMommersteeg, Mathilda T MAndrews, William DYpsilanti, Athéna RZelina, PavolYeh, Mason LNorden, JuliaKispert, AndreasChédotal, AlainChristoffels, Vincent MParnavelas, John GCirc. Res. 112:465-7522981605Pubmed2012Slits and Robo-2 regulate the coalescence of subsets of olfactory sensory neuron axons within the ventral region of the olfactory bulbCho, Jin HKam, Joseph W KCloutier, Jean-FrançoisDev. Biol. 371:269-79

Regulation of commissural axon pathfinding by SLIT and ROBO

Commissural axons project to the floor plate, attracted by the interaction of their DCC receptors with Netrin-1 (NTN1) produced by floor plate cells (Dickson and Gilestro 2006) and radial glia (Dominici et al. 2017, Varadarajan et al. 2017). Once an axon enters the floor plate, it must be efficiently expelled on the contralateral side. A switch from attraction to repulsion allows commissural axons to enter and then leave the CNS midline. Based on studies in Xenopus neurons and by yeast two hybrid screens, it is observed that the attractive response of axons to netrins is silenced by activation of ROBO. SLIT bound ROBO binds to DCC, preventing it from transducing an attractive response to netrin. The sensitivity of axons to the repulsive action of SLIT does not only depend on repulsive SLIT receptors (ROBO1 and ROBO2), but is also influenced by expression of ROBO3, a SLIT receptor that suppresses the activity of ROBO1 and ROBO2. Upon crossing the midline, commissural axons downregulate expression of ROBO3 and increase expression of ROBO1/ROBO2 (reviewed by Dickson and Gilestro, 2006). Two transcript variants of ROBO3, ROBO3.1 and ROBO3.2 are considered to play different roles in midline crossing. ROBO3.1 is expressed in the pre-crossing and crossing commissural axons, while ROBO3.2, generated by alternative splicing, is expressed after midline crossing and thought to block midline re-crossing (Chen et al. 2008). In addition to SLITs, a secreted ligand NELL2 also acts as an axonal guidance cue that, by acting through ROBO3 receptors, helps to steer commissural axons to the midline. Both ROBO3.1 and ROBO3.2 can bind to a secreted ligand NELL2. Pre-crossing commissural axons, which express ROBO3.1, are repelled by NELL2. Post-crossing axons, which express ROBO3.2 are not repelled by NELL2 (Jaworski et al. 2015). .

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23

ROBO3.1 antagonizes ROBO1/ROBO2 to allow floor plate crossing

ROBO3 antagonizes ROBO1/ROBO2 function to prevent their response to SLIT, thus allowing cells that are expressing ROBO1/ROBO2 to progress towards and across the floor plate. Exactly how ROBO3 interferes with ROBO1/ROBO2 function is not yet clear (Chen et al. 2008). It was shown that ROBO3 isoform ROBO3.1 reduces the amount of ROBO1 and ROBO2 at the cell surface and suggested that ROBO3.1 acts by directing ROBO1 and ROBO2 to late endosome- and lysosome-dependent degradation pathway (Li et al. 2014). Direct binding of ROBO3.1 to ROBO2 was demonstrated (Li et al. 2014).During commissural axon midline crossing in Drosophila, Robo1 signaling can also be antagonized with Robo2 expressed in trans. Extracellular domains of Robo1 and Robo2 may interact through their Ig domains, preventing Robo1 activation by Slits and interfering with axon repulsion (Evans et al. 2015).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-23

Converted from EntitySet in Reactome

Reactome DB_ID: 9014787

ROBO2,(ROBO1) [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityROBO2 [plasma membrane]

Reactome DB_ID: 426410

EQUAL

1386

EQUAL

Reactome DB_ID: 428496

ROBO2,(ROBO1):ROBO3.1 [plasma membrane]

ROBO2,(ROBO1):ROBO3.1

Converted from EntitySet in Reactome

Reactome DB_ID: 9014787

Reactome DB_ID: 426410

EQUAL

1386

EQUAL

Reactome Database ID Release 75428496Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428496ReactomeR-HSA-428496

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428496.3Reactome Database ID Release 75428510Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428510ReactomeR-HSA-428510

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428510.326186094Pubmed2015Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axonsEvans, Timothy ASantiago, CelineArbeille, EliseBashaw, Greg JElife 4:e0840724936616Pubmed2014Robo3.1A suppresses slit-mediated repulsion by triggering degradation of Robo2Li, LingyongLiu, ShengbingLei, YunCheng, YeYao, ChangqunZhen, XuechuJ. Neurosci. Res. 92:835-46

ROBO3 binds NELL2

Based on studies in mice, ROBO3 isoforms ROBO3.1 and ROBO3.2 bind to a secreted ligand NELL2 (neural epidermal growth factor-like-like 2). This interaction involves the EGF-like domains of NELL2 and the FN3 (FNIII) domain of ROBO3. Pre-crossing commissural axons which express ROBO3.1 are repelled by NELL2. Post-crossing axons, which express ROBO3 isoform ROBO3.2 are not repelled by NELL2, despite interaction between ROBO3.2 and NELL2. NELL1 can also bind to both ROBO3.1 and ROBO3.2, but since NELL1 is not expressed in mouse spinal cord during commissural axon guidance, these interactions are not considered to be physiologically relevant. ROBO1 and ROBO2 do not interact with NELL proteins (Jaworski et al. 2015).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Converted from EntitySet in Reactome

Reactome DB_ID: 9014794

ROBO3 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityROBO3.1 [plasma membrane]

Reactome DB_ID: 9010198

UniProt:Q99435 NELL2

NELL2

NELL2NRP2FUNCTION Required for neuron survival through the modulation of MAPK pathways (By similarity). Involved in the regulation of hypothalamic GNRH secretion and the control of puberty (By similarity).SUBUNIT Homotrimer. Binds to PKC beta-1 (By similarity).

UniProtQ99435

EQUAL

816

EQUAL

Reactome DB_ID: 9010200

NELL2:ROBO3 [plasma membrane]

NELL2:ROBO3

Converted from EntitySet in Reactome

Reactome DB_ID: 9014794

Reactome DB_ID: 9010198

EQUAL

816

EQUAL

Reactome Database ID Release 759010200Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010200ReactomeR-HSA-9010200

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010200.1Reactome Database ID Release 759010190Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010190ReactomeR-HSA-9010190

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9010190.2

DCC interaction with ROBO1

DCC and ROBO1 heterodimerize via conserved sequence elements in their cytoplasmic domains, namely CC1 (conserved cytoplasmic region1) in ROBO1 and P3 in DCC. The formation of this complex is dependent on the previous interaction between ROBO and its ligand (SLIT). This physical interaction between ROBO:SLIT and DCC silences the attractive effect of Netrin:DCC and regulates the midline crossing of axons. From the analysis of multiple double mutant combinations of the ROBO:SLIT and Netrin:DCC receptor-ligand pairs, it was deduced that ROBO repulsion on its own is sufficient to prevent commissural axons from re-crossing the midline, and that Netrin:DCC is not the only source of attraction at the midline (Stein and Tessier-Lavigne 2001, Garbe and Bashaw 2007).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Cooper, HM, 2010-02-16Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-07-30 10:24:23Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 197560

UniProt:P43146 DCC

DCC

IGDCC1DCCFUNCTION Receptor for netrin required for axon guidance. Mediates axon attraction of neuronal growth cones in the developing nervous system upon ligand binding. Its association with UNC5 proteins may trigger signaling for axon repulsion. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand. Implicated as a tumor suppressor gene.SUBUNIT Interacts with the cytoplasmic part of UNC5A, UNC5B, UNC5C and probably UNC5D (By similarity). Interacts with DSCAM (By similarity). Interacts with PTK2/FAK1 and MAPK1 (By similarity). Interacts with NTN1 (By similarity). Interacts with MYO10 (PubMed:21642953). Interacts with CBLN4; this interaction can be competed by NTN1 (By similarity). Interacts with SIAH1 and SIAH2 (PubMed:9334332).TISSUE SPECIFICITY Found in axons of the central and peripheral nervous system and in differentiated cell types of the intestine. Not expressed in colorectal tumor cells that lost their capacity to differentiate into mucus producing cells.PTM Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation.MISCELLANEOUS Inactivation of DCC due to allelic deletion and/or point mutations is related to lymphatic and hematogenous metastatic tumor dissemination.SIMILARITY Belongs to the immunoglobulin superfamily. DCC family.

UniProtP43146

EQUAL

1447

EQUAL

Reactome DB_ID: 204367

ROBO1:SLIT [plasma membrane]

ROBO1:SLIT

Converted from EntitySet in Reactome

Reactome DB_ID: 390366

SLIT [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySLIT2 [extracellular region]SLIT3 [extracellular region]SLIT1 [extracellular region]

Reactome DB_ID: 204361

EQUAL

1651

EQUAL

Reactome Database ID Release 75204367Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=204367ReactomeR-HSA-204367

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-204367.2

Reactome DB_ID: 373666

DCC:ROBO1:SLIT [plasma membrane]

DCC:ROBO1:SLIT

Reactome DB_ID: 197560

EQUAL

1447

EQUAL

Reactome DB_ID: 204367

Reactome Database ID Release 75373666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373666ReactomeR-HSA-373666

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373666.2Reactome Database ID Release 75373715Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373715ReactomeR-HSA-373715

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373715.317392474Pubmed2007Independent functions of Slit-Robo repulsion and Netrin-Frazzled attraction regulate axon crossing at the midline in DrosophilaGarbe, DSBashaw, GJJ Neurosci 27:3584-9211239147Pubmed2001Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complexStein, ETessier-Lavigne, MScience 291:1928-38

ROBO3.1 binds DCC

Based on studies in mice and biochemical studies with human DCC and mouse Robo3.1, ROBO3.1 (also known as ROBO3A.1) can bind to DCC both in the presence and absence of netrin-1 (NTN1). The two proteins interact via their intracellular domains through the P3 domain of DCC and the CC2 and CC3 motifs of ROBO3. Binding of ROBO3.1 to DCC apparently contributes to NTN1-mediated attraction of commissural axons to the midline (Zelina et al. 2014).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 373667

DCC:NTN1 [plasma membrane]

DCC:NTN1

DCC:Netrin-1

Reactome DB_ID: 197560

EQUAL

1447

EQUAL

Reactome DB_ID: 373624

UniProt:O95631 NTN1

NTN1

NTN1LNTN1FUNCTION Netrins control guidance of CNS commissural axons and peripheral motor axons. Its association with either DCC or some UNC5 receptors will lead to axon attraction or repulsion, respectively. Binding to UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion (PubMed:28483977). Involved in dorsal root ganglion axon projection towards the spinal cord (PubMed:28483977). It also serves as a survival factor via its association with its receptors which prevent the initiation of apoptosis. Involved in tumorigenesis by regulating apoptosis (PubMed:15343335).SUBUNIT Binds to its receptors; DCC, UNC5A, UNC5B, UNC5C and probably UNC5D (PubMed:9950216). Binds to its receptor; DSCAM (PubMed:19196994). Interacts with APP (By similarity).TISSUE SPECIFICITY Widely expressed in normal adult tissues with highest levels in heart, small intestine, colon, liver and prostate. Reduced expression in brain tumors and neuroblastomas. Expressed in epididymis (at protein level).

UniProtO95631

EQUAL

604

EQUAL

Reactome Database ID Release 75373667Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373667ReactomeR-HSA-373667

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373667.2

Reactome DB_ID: 426410

EQUAL

1386

EQUAL

Reactome DB_ID: 9011213

ROBO3.1:DCC:NTN1 [plasma membrane]

ROBO3.1:DCC:NTN1

Reactome DB_ID: 373667

Reactome DB_ID: 426410

EQUAL

1386

EQUAL

Reactome Database ID Release 759011213Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011213ReactomeR-HSA-9011213

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011213.1Reactome Database ID Release 759011224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011224ReactomeR-HSA-9011224

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011224.1

2.7.10

SRC phosphorylates ROBO3.1 in response to NTN1

In response to NTN1 (netrin-1)-mediated activation of DCC, based on mouse studies, SRC phosphorylates ROBO3.1 on a conserved tyrosine Y1019. The mechanism of SRC recruitment to ROBO3.1 in response to NTN1 is not known (Zelina et al. 2014). The biological significance of SRC-mediated phosphorylation of ROBO3.1 is not known.

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 9011213

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 9011242

p-Y1019-ROBO3.1:DCC:NTN1 [plasma membrane]

p-Y1019-ROBO3.1:DCC:NTN1

Reactome DB_ID: 9011239

O4'-phospho-L-tyrosine at 1019

1019

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

EQUAL

1386

EQUAL

Reactome DB_ID: 373667

Reactome Database ID Release 759011242Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011242ReactomeR-HSA-9011242

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011242.1

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 1810408

UniProt:P12931 SRC

SRC

SRCSRC1FUNCTION Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:8755529, PubMed:14585963). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances DDX58/RIG-I-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-419 increases kinase activity.SUBUNIT Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with DDEF1/ASAP1; via the SH3 domain (By similarity). Interacts with CCPG1 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts with ERBB2, STAT1 and PNN (By similarity). Interacts with DDR1, DDR2 and DAB2 (By similarity). Interacts with CDCP1, PELP1, TGFB1I1 and TOM1L2 (PubMed:12415108, PubMed:15851033, PubMed:16479011, PubMed:17202804). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (PubMed:11152665). Interacts with RALGPS1; via the SH3 domain (PubMed:10747847). Interacts with CAV2 (tyrosine phosphorylated form) (PubMed:12091389, PubMed:15504032). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with ARRB1 and ARRB2 (PubMed:10753943, PubMed:9924018). Interacts with SRCIN1 (PubMed:17525734). Interacts with NDFIP2 and more weakly with NDFIP1 (PubMed:20534535). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine) (PubMed:18657504, PubMed:21411625). Interacts with FASLG (PubMed:19807924). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14585963). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts (via SH2 and SH3 domain) with TNK2 (PubMed:21309750). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (PubMed:20100835). Interacts with TRAF3 (via RING-type zinc finger domain) (PubMed:19419966). Interacts with DDX58, MAVS and TBK1 (PubMed:19419966). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (PubMed:9584165, PubMed:11279199). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with FCAMR (PubMed:8759729). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (PubMed:18024423). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (PubMed:17293535). Interacts with TRAP1 (PubMed:23564345). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (PubMed:14661060, PubMed:22888118). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:7478590). Interacts with MPP2 (PubMed:19665017). Interacts with PRR7 (PubMed:21460222). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (PubMed:19307596). Interacts with P85 (PIK3R1 or PIK3R2) (PubMed:28903391). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (PubMed:25731159).SUBUNIT (Microbial infection) Interacts with HEV ORF3 protein; via the SH3 domain.SUBUNIT (Microbial infection) Interacts (via SH2 domain) with HCV nonstructural protein 5A (via N-terminus).TISSUE SPECIFICITY Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.DOMAIN The SH2 and SH3 domains are important for the intramolecular and intermolecular interactions that regulate catalytic activity, localization, and substrate recruitment.PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-530 by PTPRJ (By similarity). Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (PubMed:25731159).PTM S-nitrosylation is important for activation of its kinase activity.PTM Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation.DISEASE SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.

UniProtP12931

N-myristoylglycine at 2

EQUAL

N-myristoylglycine [MOD:00068]

O4'-phospho-L-tyrosine at 419

419

EQUAL

536

EQUAL

GO0004713

GO molecular function

Reactome Database ID Release 758876946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8876946Reactome Database ID Release 759011241Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011241ReactomeR-HSA-9011241

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9011241.1

Reactome Database ID Release 75428542Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428542ReactomeR-HSA-428542

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428542.328445456Pubmed2017Floor-plate-derived netrin-1 is dispensable for commissural axon guidanceDominici, ChloéMoreno-Bravo, Juan AntonioPuiggros, Sergi RoigRappeneau, QuentinRama, NicolasVieugue, PaulineBernet, AgnesMehlen, PatrickChédotal, AlainNature 545:350-35428434801Pubmed2017Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal CordVaradarajan, Supraja GKong, Jennifer HPhan, Keith DKao, Tzu-JenPanaitof, S CarmenCardin, JulieEltzschig, HolgerKania, ArturNovitch, Bennett GButler, Samantha JNeuron 94:790-799.e317029581Pubmed2006Regulation of commissural axon pathfinding by slit and its Robo receptorsDickson, BJGilestro, GFAnnu Rev Cell Dev Biol 22:651-75

Regulation of cortical dendrite branching

Besides being involved in axon repulsion during neuronal system development, SLIT-ROBO signaling is also involved in dendrite branching. Based on studies in mice, SLIT1 triggers cortical dendrite branching by activating receptors ROBO1 and/or ROBO2. ROBO effector NCK2 is needed for SLIT1-mediated dendrite branching (Round and Sun 2011).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

SLIT1 binds ROBO1,(ROBO2)

Based on mouse experiments, SLIT1 binds to ROBO1 and/or ROBO2 to stimulate cortical dendrite branching (Round and Sun 2011). SLIT1-mediated activation of ROBO1 and/or ROBO2 may also be involved in regulation of midline crossing in the spinal cord (Mambetisaeva et al. 2015). SLIT1 is expressed by new neurons in the adult brain which migrate from the subventricular zone to the olfactory bulb through the rostral migratory stream. Astrocytes in the rostral migratory stream express ROBO receptors, mostly ROBO2, but also ROBO1 and ROBO3. These ROBO-expressing astrocytes are repelled by SLIT1-expressing young migrating neurons, which results in the formation and maintenance of the astrocytic tunnels. Astrocytic tunnels allow rapid directional migration of new neurons in the adult brain (Kaneko et al. 2010). Signaling through SLIT1-ROBO2 is implicated in regulation of peripheral nerve regeneration (Zhang et al. 2010).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Converted from EntitySet in Reactome

Reactome DB_ID: 428477

Reactome DB_ID: 204359

EQUAL

1534

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8985807

SLIT1:ROBO1,ROBO2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 758985799Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985799ReactomeR-HSA-8985799

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985799.220670830Pubmed2010New neurons clear the path of astrocytic processes for their rapid migration in the adult brainKaneko, NaokoMarín, OscarKoike, MasatoHirota, YukiUchiyama, YasuoWu, Jane YLu, QiangTessier-Lavigne, MarcAlvarez-Buylla, ArturoOkano, HRubenstein, John L RSawamoto, KazunobuNeuron 67:213-2320172023Pubmed2010Slit1 promotes regenerative neurite outgrowth of adult dorsal root ganglion neurons in vitro via binding to the Robo receptorZhang, Hai YingZheng, Lin FengYi, Xi NanChen, Zhi BinHe, Zhong PingZhao, DanZhang, Xian FangMa, Zhi JianJ. Chem. Neuroanat. 39:256-6121600986Pubmed2011The adaptor protein Nck2 mediates Slit1-induced changes in cortical neuron morphologyRound, Jennifer ESun, HuiMol. Cell. Neurosci. 47:265-73

NCK2 binds to ROBO1,(ROBO2)

Based on mouse experiments, SLIT1-activated ROBO receptors ROBO1 and/or ROBO2 bind to NCK2. The interaction involves three SH3 domains of NCK2 and the PxxP-rich region between CC2 and CC3 motifs in the cytoplasmic domain of ROBO. While NCK1 can also associate with ROBO receptors, only NCK2 is implicated in SLIT1-induced cortical dendrite branching (Round and Sun 2011).

Authored: Orlic-Milacic, Marija, 2017-06-26Reviewed: Jaworski, Alexander, 2017-07-31Edited: Orlic-Milacic, Marija, 2017-06-26

Converted from EntitySet in Reactome

Reactome DB_ID: 8985807

Reactome DB_ID: 204885

UniProt:O43639 NCK2

NCK2

NCK2GRB4FUNCTION Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.SUBUNIT Interacts with DOCK1, LIMS1 and TGFB1I1. Part of a complex containing PPP1R15B, PP1 and NCK2. Interacts with FASLG (By similarity). Interacts with AXL. Interacts with PAK1, PKN2 and SOS1. Interacts (via SH2 domain) with EGFR. Interacts (via SH2 domain) with DDR1.TISSUE SPECIFICITY Ubiquitous.PTM Phosphorylated.

UniProtO43639

EQUAL

380

EQUAL

Reactome DB_ID: 8985808

SLIT1:ROBO1,ROBO2:NCK2 [plasma membrane]

SLIT1:ROBO1,ROBO2:NCK2

Converted from EntitySet in Reactome

Reactome DB_ID: 8985807

Reactome DB_ID: 204885

EQUAL

380

EQUAL

Reactome Database ID Release 758985808Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985808ReactomeR-HSA-8985808

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985808.1Reactome Database ID Release 758985812Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985812ReactomeR-HSA-8985812

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985812.1

Reactome Database ID Release 758985801Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985801ReactomeR-HSA-8985801

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985801.1

Ena/VASP proteins bind ROBO1:SLIT2 complex

Ena/VASP proteins (ENAH, EVL and VASP) are required in part for ROBO's repulsive output. Ena/VASP proteins are drawn as effectors downstream of Robo signaling via a direct interaction with ROBO. ROBO's CC2 (LPPPP) motif is the consensus binding site for the EVH1 domain of Ena/VASP proteins. The Ena/VASP family of proteins has a universal role in control of cell motility and actin dynamics. These proteins consist of an N-terminal EVH1 domain, a central proline rich region, which acts as a ligand for the actin monomer binding protein Profilin (PFN), as well as several SH3 domain-containing proteins, such as ABL, and a C-terminal EVH2 domain involved in oligomerization and F-actin binding (Bashaw et al. 2000).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 428478

Ena/VASP Proteins [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityENAH [cytosol]VASP [cytosol]EVL [cytosol]

UniProtQ8N8S7UniProtP50552UniProtQ9UI08

Reactome DB_ID: 376032

SLIT2:ROBO1:Ena/VASP proteins [plasma membrane]

SLIT2:ROBO1:Ena/VASP proteins

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 428478

Reactome Database ID Release 75376032Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376032ReactomeR-HSA-376032

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376032.3Reactome Database ID Release 75376140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376140ReactomeR-HSA-376140

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376140.210892742Pubmed2000Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptorBashaw, GJKidd, ThomasMurray, DPawson, TGoodman, CSCell 101:703-15

Recruitment of Profilin by Ena/VASP proteins

Ena/VASP proteins (ENAH, EVL1 and VASP) enhance actin filament elongation via the recruitment of profilin:actin complexes to the tips of spreading lamellipodia. Profilin (PFN1 or PFN2) binds to the central proline rich domain of an Ena/VASP protein (Bashaw et al. 2000).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 376032

Converted from EntitySet in Reactome

Reactome DB_ID: 203077

PFN [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 428492

SLIT2:ROBO1:Ena/VASP:PFN [plasma membrane]

SLIT2:ROBO1:Ena/VASP:PFN

Reactome DB_ID: 376032

Converted from EntitySet in Reactome

Reactome DB_ID: 203077

Reactome Database ID Release 75428492Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428492ReactomeR-HSA-428492

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428492.3Reactome Database ID Release 75428534Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428534ReactomeR-HSA-428534

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428534.2

Inactivation of CDC42 and RAC1

Rho family GTPases, including RAC1, RHOA, and CDC42, are ideal candidates to regulate aspects of cytoskeletal dynamics downstream of axon guidance receptors. Biochemical and genetic studies have revealed an important role for CDC42 and RAC1 in ROBO repulsion. ROBO controls the activity of Rho GTPases by interacting with a family of SLIT/ROBO-specific GAPs (SrGAPs) and Vilse/CrossGAP. SrGAPs inactivate CDC42 and Vilse/CrossGAP specifically inactivates RAC1. It was recently implicated that SRGAP3 may inactivate RAC1 downstream of SLIT1-activated ROBO2, which promotes neurite outgrowth in mammalian dorsal root ganglion (DRG) neurons (Zhang et al. 2014).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

SRGAP binds ROBO1:SLIT2

The ROBO1 receptor regulates Rho GTPase activity through a ligand-dependent association with members of a GAP protein family called SRGAPs (SLIT-ROBO GAPs), SRGAP1, SRGAP2 and SRGAP3 (Wong et al. 2001, Bacon et al. 2011). Extracellular interaction between SLIT and ROBO increases the intracellular interaction between the CC3 motif of ROBO1 and the SH3 motif of the SRGAPs (Wong et al. 2001).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 428474

SRGAP [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySRGAP2 [cytosol]SRGAP1 [cytosol]SRGAP3 [cytosol]

UniProtO75044UniProtQ7Z6B7UniProtO43295

Reactome DB_ID: 376031

SLIT2:ROBO1:SRGAP [plasma membrane]

SLIT2:ROBO1:SRGAP

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 428474

Reactome Database ID Release 75376031Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376031ReactomeR-HSA-376031

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376031.4Reactome Database ID Release 75376145Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376145ReactomeR-HSA-376145

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376145.211672528Pubmed2001Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathwayWong, KRen, XRHuang, YZXie, YLiu, GSaito, HTang, HWen, LBrady-Kalnay, SMMei, LWu, Jer-YuarnXiong, WCRao, YCell 107:209-21

Inactivation of CDC42

SRGAP bound to ROBO's cytoplasmic tail increases the intrinsic GTPase activity of CDC42, converting the GTP-bound form of CDC42 into its GDP-bound form, therefore inactivating CDC42. Inactivation of CDC42 leads to a reduction in the activation of the Neuronal Wiskott-Aldrich Syndrome protein (NWASP), thus decreasing the level of the active Arp2/3 complex. Because active Arp2/3 promotes actin polymerization, the reduction of active CDC42 eventually decreases actin polymerization. SLIT regulates SRGAP interaction with ROBO1 and CDC42, increasing SRGAP binding to CDC42 (Wong et al. 2001, Li et al. 2006).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 29356

Reactome DB_ID: 182921

CDC42:GTP [plasma membrane]

CDC42:GTP

CDC42-GTP

Reactome DB_ID: 29438

GTP [ChEBI:15996]

GTP

Guanosine 5'-triphosphate

ChEBI15996

Reactome DB_ID: 449545

UniProt:P60953 CDC42

CDC42

CDC42FUNCTION Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (PubMed:15642749). Regulates cell migration (PubMed:17038317). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (PubMed:14978216). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. Facilitates filopodia formation upon DOCK11-activation (By similarity). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (PubMed:26465210).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase.SUBUNIT Interacts with CDC42EP1, CDC42EP2, CDC42EP3, CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, PARD6A, PARD6B and PARD6G (in a GTP-dependent manner) (PubMed:10490598, PubMed:10816584, PubMed:10954424, PubMed:11260256). Interacts with activated CSPG4 and with BAIAP2 (PubMed:10587647, PubMed:11130076). Interacts with activated CSPG4 and with BAIAP2 (By similarity). Interacts with DOCK11/Zizimin2; the interaction activates CDC42 by exchanging GDP for GTP (By similarity). Interacts with DOCK9; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552, PubMed:19745154). Interacts with DOCK8 (via DHR-2 domain); the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552). Interacts with IQGAP1 (By similarity). Interacts with NET1 and ARHGAP33/TCGAP (By similarity). Part of a complex with PARD3, PARD6A or PARD6B and PRKCI or PRKCZ (PubMed:11260256). The GTP-bound form interacts with CCPG1 (By similarity). Interacts with USP6 (PubMed:12612085). Interacts with NEK6 (PubMed:20873783). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas (PubMed:17038317). Interacts with ITGB1BP1 (PubMed:11807099). Interacts with ARHGDIA; this interaction inactivates and stabilizes CDC42 (PubMed:23434736). Interacts with ARHGDIB; this maintains CDC42 in the inactive, GDP-bound form (PubMed:7512369). Interacts (in GTP-bound form) with FNBP1L and ABI1, but only in the presence of FNBP1L (PubMed:19798448). May interact with ARHGEF16; responsible for the activation of CDC42 by the viral protein HPV16 E6 (PubMed:21139582).PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM Phosphorylated by SRC in an EGF-dependent manner, this stimulates the binding of the Rho-GDP dissociation inhibitor RhoGDI.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of CDC42 and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).SIMILARITY Belongs to the small GTPase superfamily. Rho family. CDC42 subfamily.

UniProtP60953

EQUAL

188

EQUAL

Reactome Database ID Release 75182921Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=182921ReactomeR-HSA-182921

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-182921.1

Reactome DB_ID: 418830

CDC42:GDP [cytosol]

CDC42:GDP

Reactome DB_ID: 29420

Reactome DB_ID: 442630

EQUAL

188

EQUAL

Reactome Database ID Release 75418830Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=418830ReactomeR-HSA-418830

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-418830.1

Reactome DB_ID: 29372

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

[PO3(OH)](2-)HYDROGENPHOSPHATE IONhydrogen phosphate[P(OH)O3](2-)HPO4(2-)phosphateINORGANIC PHOSPHATE GROUP

ChEBI43474PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 376031

GO0005096

GO molecular function

Reactome Database ID Release 75428514Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428514Reactome Database ID Release 75428533Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428533ReactomeR-HSA-428533

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428533.316857672Pubmed2006Structural basis of Robo proline-rich motif recognition by the srGAP1 Src homology 3 domain in the Slit-Robo signaling pathwayLi, XChen, YLiu, YGao, JGao, FBartlam, MarkWu, Jer-YuarnRao, ZiheJ Biol Chem 281:28430-7

ARHGAP39 (Vilse) binds ROBO1:SLIT2

Vilse/CrossGAP (CrGAP), a conserved Rac-specific GAP in Drosophila, is involved in Robo mediated repulsion. CrGAP directly interacts with Robo, both biochemically and genetically. The biochemical interaction is mediated by the WW domains in CrGAP and the CC2 motif of Robo. The human homologue of Vilse/CrGAP, ARHGAP39 (also known as KIAA1688), was identified. ARHGAP39 shares 54.4% sequence identity with Drosophila CrGAP and is referred to as human Vilse/CrGAP protein (Lundstrom et al. 2004, Hu et al. 2005).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 390371

Reactome DB_ID: 200631

UniProt:Q9C0H5 ARHGAP39

ARHGAP39

KIAA1688ARHGAP39SIMILARITY Contains 1 MyTH4 domain.SIMILARITY Contains 1 Rho-GAP domain.SIMILARITY Contains 2 WW domains.

UniProtQ9C0H5

EQUAL

1083

EQUAL

Reactome DB_ID: 428491

ROBO1:SLIT2:ARHGAP39 [plasma membrane]

ROBO1:SLIT2:ARHGAP39

Robo1:Slit2:KIAA1688

Reactome DB_ID: 390371

Reactome DB_ID: 200631

EQUAL

1083

EQUAL

Reactome Database ID Release 75428491Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428491ReactomeR-HSA-428491

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428491.3Reactome Database ID Release 75428536Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428536ReactomeR-HSA-428536

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428536.215755809Pubmed2005Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsionHu, HLi, MLabrador, JPMcEwen, JLai, ECGoodman, CSBashaw, GJProc Natl Acad Sci U S A 102:4613-815342493Pubmed2004Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axonsLundström, AGallio, MEnglund, CSteneberg, PHemphälä, JAspenström, PKeleman, KFalileeva, LDickson, BJSamakovlis, CGenes Dev 18:2161-71

Inactivation of RAC1

Vilse and its human homolog ARHGAP39 bind directly to the intracellular domains of the corresponding ROBO receptors and promote the hydrolysis of GTP bound to RAC1 (Lundstrom et al. 2004, Hu et al. 2005).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 29356

Reactome DB_ID: 442641

RAC1:GTP [plasma membrane]

RAC1:GTP

Reactome DB_ID: 351141

UniProt:P63000 RAC1

RAC1

TC25RAC1MIG5FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:1643658, PubMed:28886345). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (PubMed:9121475). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:1643658). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity (By similarity). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3.FUNCTION Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (PubMed:31285585, PubMed:30250061). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with GARRE1 (PubMed:31871319).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium (PubMed:7777059, PubMed:7775453, PubMed:8626575, PubMed:19744486, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).SIMILARITY Belongs to the small GTPase superfamily. Rho family.

UniProtP63000

EQUAL

189

EQUAL

Reactome DB_ID: 29438

Reactome Database ID Release 75442641Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442641ReactomeR-HSA-442641

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442641.1

Reactome DB_ID: 5674631

RAC1:GDP [plasma membrane]

RAC1:GDP

Reactome DB_ID: 351141

EQUAL

189

EQUAL

Reactome DB_ID: 29420

Reactome Database ID Release 755674631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5674631ReactomeR-HSA-5674631

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5674631.1

Reactome DB_ID: 29372

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 428491

Reactome Database ID Release 75428516Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428516Reactome Database ID Release 75428522Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428522ReactomeR-HSA-428522

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428522.4

Reactome Database ID Release 75428543Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428543ReactomeR-HSA-428543

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428543.225149377Pubmed2014srGAP3 promotes neurite outgrowth of dorsal root ganglion neurons by inactivating RAC1Zhang, Quan-PengZhang, Hai-YingZhang, Xian-FangZhao, Jiu-HongMa, Zhi-JianZhao, DanYi, Xi-NanAsian Pac J Trop Med 7:630-8

Activation of RAC1

A low level of RAC1 activity is essential to maintain axon outgrowth. ROBO activation recruits SOS, a dual specificity GEF, to the plasma membrane via Dock homolog NCK (NCK1 or NCK2) to activate RAC1 during midline repulsion.

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

NCK binds ROBO1:SLIT2

SLIT stimulation recruits SH3-SH2 adaptor protein Dreadlocks (Dock) (NCK in vertebrates) to the ROBO1 receptor. This interaction involves the CC2 and CC3 motifs of ROBO1 (Fan et al. 2003, Ang et al. 2003).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 381949

NCK1,NCK2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNCK1 [cytosol]NCK2 [cytosol]

UniProtP16333

Reactome DB_ID: 428486

SLIT2:ROBO1:NCK [plasma membrane]

SLIT2:ROBO1:NCK

Nck:Robo1:Slit2

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 381949

Reactome Database ID Release 75428486Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428486ReactomeR-HSA-428486

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428486.4Reactome Database ID Release 75428511Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428511ReactomeR-HSA-428511

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428511.312588847Pubmed2003Dock and Pak regulate olfactory axon pathfinding in DrosophilaAng, LHKim, JStepensky, VHing, HDevelopment 130:1307-1614527437Pubmed2003Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midlineFan, XLabrador, JPHing, HBashaw, GJNeuron 40:113-27

Recruitment of PAK to NCK

NCK1 or NCK2, orthologues of Drosophila Dock, bound to ROBO1 receptor, recruits PAK to specific sites at the growth cone membrane, where PAK, activated by RAC1, regulates the recycling and retrograde flow of actin filaments. In mammals, there are six PAK isoforms (PAK1-6) and PAK binds to the 2nd SH3 domain of NCK with its proline rich PxxP motif (Galisteo et al. 1996, Fan et al. 2003). PAK autophosphorylation triggered by RAC1/CDC42 activation disrupts PAK interaction with NCK proteins (Zhao et al. 2000).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 428486

Converted from EntitySet in Reactome

Reactome DB_ID: 428475

PAK [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 428482

SLIT2:ROBO1:NCK:PAK [plasma membrane]

SLIT2:ROBO1:NCK:PAK

Reactome DB_ID: 428486

Converted from EntitySet in Reactome

Reactome DB_ID: 428475

Reactome Database ID Release 75428482Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428482ReactomeR-HSA-428482

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428482.3Reactome Database ID Release 75428531Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428531ReactomeR-HSA-428531

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428531.310805734Pubmed2000Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylationZhao, Z SManser, ELim, LMol. Cell. Biol. 20:3906-17

Recruitment of SOS to plasma membrane

Upon SLIT-mediated ROBO stimulation, SOS1 or SOS2 is recruited into the multiprotein complex consisting of SLIT2, ROBO1 and the SH3-SH2 protein NCK1 or NCK2 (orthologues of Drosophila Dock). NCK bridges the physical association between ROBO and SOS. This interaction was demonstrated in both Drosophila and human cells (Hu et al. 1995, Fritz et al. 2000, Yang and Bashaw 2006).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 428486

Converted from EntitySet in Reactome

Reactome DB_ID: 167215

SOS [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySOS1 [cytosol]SOS2 [cytosol]

UniProtQ07889UniProtQ07890

Reactome DB_ID: 428481

SLIT2:ROBO1:NCK:SOS [plasma membrane]

SLIT2:ROBO1:NCK:SOS

Reactome DB_ID: 428486

Converted from EntitySet in Reactome

Reactome DB_ID: 167215

Reactome Database ID Release 75428481Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428481ReactomeR-HSA-428481

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428481.4Reactome Database ID Release 75428515Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428515ReactomeR-HSA-428515

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428515.317114045Pubmed2006Son of sevenless directly links the Robo receptor to rac activation to control axon repulsion at the midlineYang, LBashaw, GJNeuron 52:595-6077862111Pubmed1995Binding of NCK to SOS and activation of ras-dependent gene expressionHu, QMilfay, DWilliams, LTMol Cell Biol 15:1169-74

Activation of RAC1 by SOS

SOS (SOS1 or SOS2), bound to Dock orholog NCK (NCK1 or NCK2), has a Rac GEF activity and activates RAC1. Son of sevenless (SOS) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. The Ras and Rac-GEF activities of Sos can be uncoupled during ROBO-mediated axon repulsion; SOS axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity (Yang and Bashaw 2006).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 29438

Reactome DB_ID: 5674631

Reactome DB_ID: 29420

Reactome DB_ID: 442641

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 428481

GO0030676

GO molecular function

Reactome Database ID Release 75428513Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428513Reactome Database ID Release 75428535Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428535ReactomeR-HSA-428535

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428535.3

Reactome Database ID Release 75428540Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428540ReactomeR-HSA-428540

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428540.4GO0016601

GO biological process

Role of ABL in ROBO-SLIT signaling

ABL (ABL1 or ABL2) plays a dual role in the ROBO pathway. As a key enzymatic component in the signaling pathway, ABL supports repellent signaling (by recruiting the necessary actin binding proteins) and also feeds back on the receptor (by down regulating through phosphorylation) to adjust the sensitivity of the pathway. ABL cooperates with multiple effectors, including the actin binding protein Capulet (Capt) and Orbit/MAST/CLASP, suggesting that ABL simultaneously coordinates the dynamics of two major cytoskeletal systems to achieve growth cone repellent guidance.

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Interaction of ABL with ROBO1:SLIT2

ABL (ABL1 or ABL2) binds directly, via its SH3 domain, to the CC3 motif in the cytoplasmic domain of human ROBO1 (Bashaw et al. 2000).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 376002

ABL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityABL1 [cytosol]ABL2 [cytosol]

UniProtP00519UniProtP42684

Reactome DB_ID: 428873

SLIT2:ROBO1:ABL [plasma membrane]

SLIT2:ROBO1:ABL

Reactome DB_ID: 390371

Converted from EntitySet in Reactome

Reactome DB_ID: 376002

Reactome Database ID Release 75428873Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428873ReactomeR-HSA-428873

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428873.3Reactome Database ID Release 75376141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376141ReactomeR-HSA-376141

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376141.3

2.7.10

Phosphorylation of ROBO1 by ABL kinase

ABL kinase (ABL1 or ABL2) phosphorylates the tyrosine residue Y1073 of the conserved CC1 motif (PTPYATT) in human ROBO1 (Bashaw et al. 2000).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Reactome DB_ID: 428873

Reactome DB_ID: 113592

Reactome DB_ID: 376027

SLIT2:p-Y1073-ROBO1:ABL [plasma membrane]

SLIT2:p-Y1073-ROBO1:ABL

Reactome DB_ID: 428499

p-Y1073-ROBO1:SLIT2 [plasma membrane]

p-Y1073-ROBO1:SLIT2

Reactome DB_ID: 375997

EQUAL

1529

EQUAL

Reactome DB_ID: 375979

O4'-phospho-L-tyrosine at 1073

1073

EQUAL

1651

EQUAL

Reactome Database ID Release 75428499Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428499ReactomeR-HSA-428499

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428499.3Converted from EntitySet in Reactome

Reactome DB_ID: 376002

Reactome Database ID Release 75376027Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376027ReactomeR-HSA-376027

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376027.3

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 428873

Reactome Database ID Release 75376138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376138Reactome Database ID Release 75428888Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428888ReactomeR-HSA-428888

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428888.2

Activation of CLASP

CLASP (CLASP1 or CLASP2) acts positively downstream of ABL (ABL1 or ABL2) as part of the repellent response initiated by activation of ROBO1. CLASP is spatially positioned to interact with ROBO receptors. SLIT mediated repulsion results in activation of CLASP, presumably through its phosphorylation by the ABL kinase. Activation of CLASP in turn results in inhibition of microtubule polymerization on the side of the growth cone receiving the repulsive signal and consequently the growth cone turns to the opposite side. A direct link between ABL and CLASP, notably the mechanism of CLASP activation, has not been demonstrated, however (Wills et al. 2002, Lee et al. 2004, Kalil and Dent 2004).

Authored: Garapati, P V, 2008-09-05 06:02:05Reviewed: Kidd, T, 2009-08-18Reviewed: Jaworski, Alexander, 2017-07-31Edited: Garapati, P V, 2008-09-05 06:02:05Edited: Orlic-Milacic, Marija, 2017-06-26

Converted from EntitySet in Reactome

Reactome DB_ID: 428867

CLASP [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCLASP2 [cytosol]CLASP1 [cytosol]

UniProtO75122UniProtQ7Z460

Reactome DB_ID: 428873

Reactome DB_ID: 428876