BioPAX pathway converted from "Signaling by TGFB family members" in the Reactome database.

Signaling by TGFB family members

The human genome encodes 33 TGF-beta family members, including TGF-beta itself, as well as bone morphogenetic protein (BMP), activin, nodal and growth and differentiation factors (GDFs). This superfamily of ligands generally binds as dimers to hetero-tetrameric cell-surface receptor serine/threonine kinases to activate SMAD-dependent and SMAD-independent signaling (reviewed in Morikawa et al, 2016; Budi et al, 2017). Signaling by the TGF-beta receptor complex is initiated by TGF-beta. TGF-beta (TGFB1), secreted as a homodimer, binds to TGF-beta receptor II (TGFBR2), inducing its dimerization and formation of a stable hetero-tetrameric complex with TGF-beta receptor I homodimer (TGFBR1). TGFBR2-mediated phosphorylation of TGFBR1 triggers internalization of the heterotetrameric TGF beta receptor complex (TGFBR) into clathrin coated endocytic vesicles and recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates SMAD2 and SMAD3, promoting their association with SMAD4 (known as Co-SMAD). In the nucleus, the SMAD2/3:SMAD4 heterotrimer binds target DNA elements and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation. For a review of TGF-beta receptor signaling, please refer to Kang et al. 2009. Signaling by BMP is triggered by bone morphogenetic proteins (BMPs). BMPs can bind type I receptors in the absence of type II receptors, but the presence of both types dramatically increases binding affinity. The type II receptor kinase transphosphorylates the type I receptor, leading to recruitment and phosphorylation of SMAD1, SMAD5 and SMAD8, which function as R-SMADs in BMP signalling pathways. Phosphorylated SMAD1, SMAD5 and SMAD8 form heterotrimeric complexes with SMAD4, the only Co-SMAD in mammals. The SMAD1/5/8:SMAD4 heterotrimer regulates transcription of genes involved in development of many tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. For review of BMP signaling, please refer to Miyazono et al. 2010. Signaling by activin is triggered when an activin dimer (activin A, activin AB or activin B) binds the type II receptor (ACVR2A, ACVR2B). This complex then interacts with the type I receptor (ACVR1B, ACVR1C) and phosphorylates it. The phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes. For a review of activin signaling, please refer to Chen et al. 2006.

Authored: Rothfels, Karen, 2017-05-23Reviewed: D'Eustachio, Peter, 2017-06-22Edited: Rothfels, Karen, 2017-05-23

Signaling by TGF-beta Receptor Complex

Transforming Growth Factor (TGF) beta signalingThe TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases. TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1. The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex. In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner. The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2006-04-18 13:31:36Edited: Jassal, B, 2012-04-10

TGF-beta receptor signaling activates SMADs

Binding of transforming growth factor beta 1 (TGF beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010). Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997). Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1. In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008). The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004). SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2012-04-10

3.4.21

Latent TGF-beta-1 is cleaved by furin

In the Golgi apparatus, TGF-beta-1 (TGFB1) is activated by furin protease cleavage of the N-terminal pro-peptide portion. This leads to the formation of the N-terminal disulphide-linked dimeric pro-peptides, also known as latency-associated proteins (LAPs) and the C-terminal mature disulphide-linked dimeric TGF-beta-1. However, the N- and C-terminal polypeptides do not physically separate. Rather they stay in one complex. In addition, the LAP forms disulphide links with separate secreted proteins, the Latent TGF-beta binding proteins (LTBPs). LTBPs-linked to LAP and the non-covalently linked mature TGF-beta-1 remain together and form the large latent complex (LLC)

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-01-18 10:19:52

Reactome DB_ID: 171260

Golgi lumenGO0005796Pre-TGFB1 complex [Golgi lumen]

Pre-TGFB1 complex

TGF-beta 1 precursor complex

Reactome DB_ID: 114705

UniProt:P01137 TGFB1

TGFB1

TGFB1TGFBFUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.FUNCTION Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809).SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Latency-associated peptide: Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (Probable). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Transforming growth factor beta-1: Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtP01137

Chain Coordinates

EQUAL

390

EQUAL

Reactome Database ID Release 75171260Database 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=171260ReactomeR-HSA-171260

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-171260.2

Reactome DB_ID: 177102

Large latent complex of TGFB1 [Golgi lumen]

Large latent complex of TGFB1

Large latent complex of TGF-beta 1

Reactome DB_ID: 177108

279

EQUAL

390

EQUAL

Reactome Database ID Release 75177102Database 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=177102ReactomeR-HSA-177102

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-177102.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 157049

Golgi membraneGO0000139

UniProt:P09958 FURIN

FURIN

FURPACEFURINPCSK3FUNCTION Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999).FUNCTION (Microbial infection) Probably cleaves and activates anthrax and diphtheria toxins.FUNCTION (Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin.FUNCTION (Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.FUNCTION (Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells.ACTIVITY REGULATION Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK) (PubMed:32362314).SUBUNIT Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585).TISSUE SPECIFICITY Seems to be expressed ubiquitously.DOMAIN Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.PTM The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.PTM Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.SIMILARITY Belongs to the peptidase S8 family. Furin subfamily.

UniProtP09958

108

EQUAL

794

EQUAL

GO0004252

GO molecular function

Reactome Database ID Release 75156993Database 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=156993Reactome Database ID Release 75170844Database 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=170844ReactomeR-HSA-170844

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-170844.17737999Pubmed1995Processing of transforming growth factor beta 1 precursor by human furin convertaseDubois, CMLaprise, MHBlanchette, FGentry, LELeduc, RJ Biol Chem 270:10618-2412482908Pubmed2003Making sense of latent TGFbeta activationAnnes, JPMunger, JSRifkin, DBJ Cell Sci 116:217-24

Secretion and activation of the latent large complex of TGF-beta-1

The large latent complex (LLC) of TGF-beta-1 (TGFB1) is secreted by exocytosis to the extracellular region. TGF-beta-1 in the LLC cannot interact with the receptors and for this reason we say that it requires "activation". This means release from the LLC. This release is achieved by many mechanisms: proteolytic cleavage of the LTBPs, thrombospondin-1 binding to the LLC, integrin alphaV-beta6 binding to the LLC, reactive oxygen species and low pH. The release of mature dimeric TGF-beta-1 is essentially a mechanical process that demands cleavage and opening of the LLC structure so that the caged mature C-terminal TGF-beta-1 polypeptide is released to reach the receptor.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-03-22 11:41:32

Reactome DB_ID: 177102

Reactome DB_ID: 170852

extracellular regionGO0005576Dimeric TGFB1 [extracellular region]

Dimeric TGFB1

Dimeric TGF-beta 1

Reactome DB_ID: 170838

279

EQUAL

390

EQUAL

Reactome Database ID Release 75170852Database 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=170852ReactomeR-HSA-170852

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-170852.1Reactome Database ID Release 75177107Database 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=177107ReactomeR-HSA-177107

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-177107.115564041Pubmed2004TGF-beta activation by traction?Keski-Oja, JKoli, Kvon Melchner, HTrends Cell Biol 14:657-9

Dimeric TGF-beta-1 binds to the receptor

Dimeric TGFB1 binds to TGFBR2 homodimerThe mature dimeric TGF-beta-1 (TGFB1) binds with high affinity to its signaling receptor, the type II receptor serine/threonine kinase (TGFBR2) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). While type II receptor can form dimeric complexes in the absence of TGFB1 when overexpressed, it predominantly exists as a monomer on the surface of unstimulated cells under physiological conditions, and dimerization of TGFBR2 is triggered by TGFB1 binding (Zhang et al. 2009).

Reactome DB_ID: 170852

Reactome DB_ID: 170842

plasma membraneGO0005886

UniProt:P37173 TGFBR2

TGFBR2

TGFBR2FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.SUBUNIT Homodimer. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGFRB1 and TGFRB2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with DAXX. Interacts with TCTEX1D4. Interacts with ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with and is activated by SCUBE3; this interaction does not affect TGFB1-binding to TGFBR2. Interacts with VPS39; this interaction is independent of the receptor kinase activity and of the presence of TGF-beta. Interacts with CLU (PubMed:8555189).PTM Phosphorylated on a Ser/Thr residue in the cytoplasmic domain.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.

UniProtP37173

EQUAL

567

EQUAL

Reactome DB_ID: 170865

Dimeric TGFB1:TGFBR2 homodimer [plasma membrane]

Dimeric TGFB1:TGFBR2 homodimer

Dimeric TGF-beta1:type II receptor complex

Reactome DB_ID: 170866

TGFBR2 homodimer [plasma membrane]

TGFBR2 homodimer

Type II receptor complex

Reactome DB_ID: 170842

EQUAL

567

EQUAL

Reactome Database ID Release 75170866Database 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=170866ReactomeR-HSA-170866

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-170866.1

Reactome DB_ID: 170852

Reactome Database ID Release 75170865Database 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=170865ReactomeR-HSA-170865

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-170865.1Reactome Database ID Release 75170861Database 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=170861ReactomeR-HSA-170861

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-170861.28242743Pubmed1993Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptorFranzen, Pten Dijke, PIchijo, HYamashita, HSchulz, PHeldin, Carl-HenrikMiyazono, KCell 75:681-9219720988Pubmed2009Single-molecule imaging reveals transforming growth factor-beta-induced type II receptor dimerizationZhang, WJiang, YaxinWang, QiangMa, XinyongXiao, ZeyuZuo, WeiFang, XiaohongChen, Ye-GuangProc. Natl. Acad. Sci. U.S.A. 106:15679-837693660Pubmed1993The transforming growth factor beta receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligandMoustakas, ALin, HYHenis, YIPlamondon, JO'Connor-McCourt, MDLodish, HFJ Biol Chem 268:22215-81333888Pubmed1992TGF beta signals through a heteromeric protein kinase receptor complexWrana, JLAttisano, LCarcamo, JZentella, ADoody, JLaiho, MWang, XFMassague, JCell 71:1003-14

TGFBR2 recruits TGFBR1

Type II receptor recruits type I receptorThe protein complex of dimeric TGF-beta-1 with the type II receptor dimer (dimeric TGFB1:TGFBR2 homodimer) recruits the low affinity receptor, type I receptor (TGFBR1), thus forming a hetero-tetrameric receptor bound to the dimeric ligand on the extracellular face of the plasma membrane (TGFB1:TGFBR2:TGFBR1) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase, forms a complex with TGFBR1 and prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). TGFBR1 can homodimerize in the absence of TGFB1 when overexpressed, but under physiological conditions it exists as a monomer on the surface of unstimulated cells. TGFB1-induced dimerization of TGFBR1 is TGFBR2-dependent (Zhang et al. 2010).

Reactome DB_ID: 170865

Reactome DB_ID: 2187279

TGFBR1:FKBP1A [plasma membrane]

TGFBR1:FKBP1A

Reactome DB_ID: 170839

UniProt:P36897 TGFBR1

TGFBR1

ALK5SKR4TGFBR1FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.ACTIVITY REGULATION Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor.SUBUNIT Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. Interacts with USP15 and VPS39. Interacts with SDCBP (via C-terminus) (PubMed:25893292) Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (PubMed:25893292). Interacts with APPL1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).TISSUE SPECIFICITY Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292).PTM Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abrogates FKBP1A-binding.PTM N-Glycosylated.PTM Ubiquitinated; undergoes ubiquitination catalyzed by several E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results in the proteasomal and/or lysosomal degradation of the receptor thereby negatively regulating its activity. Deubiquitinated by USP15, leading to stabilization of the protein and enhanced TGF-beta signal. Its ubiquitination and proteasome-mediated degradation is negatively regulated by SDCBP (PubMed:25893292).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.CAUTION One report originally reported variant Ile-375 (PubMed:22113417). This variant has been subsequently corrected to Arg-375 by the same authors (Ref.49).

UniProtP36897

EQUAL

503

EQUAL

Reactome DB_ID: 2026007

cytosolGO0005829

UniProt:P62942 FKBP1A

FKBP1A

FKBP1AFKBP1FKBP12FUNCTION Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.ACTIVITY REGULATION Inhibited by both FK506 and rapamycin.SUBUNIT Interacts with TGFBR1; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation (PubMed:9233797). Interacts with ACVR1B and SMAD7 (PubMed:16720724). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts directly with RYR2 and RYR3 (PubMed:10358090, PubMed:22100703). Interacts with GLMN; rapamycin and FK506 abolish the interaction with GLMN in a dose dependent manner (PubMed:8955134). Interacts directly with RYR1 (By similarity).SIMILARITY Belongs to the FKBP-type PPIase family. FKBP1 subfamily.

UniProtP62942

EQUAL

108

EQUAL

Reactome Database ID Release 752187279Database 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=2187279ReactomeR-HSA-2187279

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-2187279.1

Reactome DB_ID: 170840

TGFB1:TGFBR2:TGFBR1 [plasma membrane]

TGFB1:TGFBR2:TGFBR1

TGF-beta 1:type II receptor:type I receptor complex

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Reactome DB_ID: 170864

TGFBR1 homodimer [plasma membrane]

TGFBR1 homodimer

Type I receptor dimer

Reactome DB_ID: 170839

EQUAL

503

EQUAL

Reactome Database ID Release 75170864Database 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=170864ReactomeR-HSA-170864

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-170864.1Reactome Database ID Release 75170840Database 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=170840ReactomeR-HSA-170840

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-170840.1

Reactome DB_ID: 2026007

EQUAL

108

EQUAL

Reactome Database ID Release 75170846Database 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=170846ReactomeR-HSA-170846

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-170846.220625381Pubmed2010Monomeric type I and type III transforming growth factor-? receptors and their dimerization revealed by single-molecule imagingZhang, WYuan, JingheYang, YongXu, LiWang, QiangZuo, WeiFang, XiaohongChen, Ye-GuangCell Res. 20:1216-239233797Pubmed1997Mechanism of TGFbeta receptor inhibition by FKBP12Chen, YGLiu, FangMassague, JEMBO J 16:3866-76

TGFBR2 phosphorylates TGFBR1

Type II receptor phosphorylates type I receptorFormation of the hetero-tetrameric TGF-beta-1 receptor complex induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. The constitutively active type II receptor kinase (which auto-phosphorylates in the absence of ligand), trans-phosphorylates specific serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of the type I receptor (Wrana et al. 1994, Souchelnytskyi et al. 1996). In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta-1 stimulation. Sumoylation enhances TGFBR1 function by facilitating recruitment and phosphorylation of SMAD3 (Kang et al. 2008).

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-01-18 10:19:52

Reactome DB_ID: 170840

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 170841

TGFB1:TGFBR2:p-TGFBR1 [plasma membrane]

TGFB1:TGFBR2:p-TGFBR1

TGF-beta 1:type II receptor:Phospho-type I receptor complex

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Reactome DB_ID: 170863

p-TGFBR1 [plasma membrane]

p-TGFBR1

Phospho-TGF-beta I receptor complex

Reactome DB_ID: 170849

O-phospho-L-serine at 165

165

EQUAL

O-phospho-L-serine [MOD:00046]

O-phospho-L-threonine at 185

185

EQUAL

O-phospho-L-threonine [MOD:00047]

O-phospho-L-threonine at 186

186

EQUAL

O-phospho-L-serine at 187

187

EQUAL

O-phospho-L-serine at 189

189

EQUAL

O-phospho-L-serine at 191

191

EQUAL

503

EQUAL

Reactome Database ID Release 75170863Database 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=170863ReactomeR-HSA-170863

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-170863.1Reactome Database ID Release 75170841Database 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=170841ReactomeR-HSA-170841

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-170841.1

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 170840

GO0005026

GO molecular function

Reactome Database ID Release 75170856Database 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=170856Reactome Database ID Release 75170843Database 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=170843ReactomeR-HSA-170843

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-170843.118469808Pubmed2008The type I TGF-beta receptor is covalently modified and regulated by sumoylationKang, Jong SeokSaunier, Elise FAkhurst, Rosemary JDerynck, RikNat. Cell Biol. 10:654-648947046Pubmed1996Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responsesSouchelnytskyi, Sten Dijke, PMiyazono, KHeldin, Carl-HenrikEMBO J 15:6231-408047140Pubmed1994Mechanism of activation of the TGF-beta receptorWrana, JLAttisano, LWieser, RVentura, FMassague, JNature 370:341-7

An anchoring protein, ZFYVE9 (SARA), recruits SMAD2/3

The activated TGF-beta receptor complex is internalized by clathrin-mediated endocytosis into early endosomes. ZFYVE9 (SARA) resides in the membrane of early endosomes. Crystallographic studies suggest that dimeric SARA in the early endosome coordinates two R-SMAD molecules (SMAD2 and/or SMAD3) per one receptor complex.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-01-18 10:19:52

Reactome DB_ID: 170841

Reactome DB_ID: 206180

early endosome membraneGO0031901

UniProt:O95405-1 ZFYVE9

ZFYVE9

ZFYVE9MADHIPSMADIPSARAFUNCTION Early endosomal protein that functions to recruit SMAD2/SMAD3 to intracellular membranes and to the TGF-beta receptor. Plays a significant role in TGF-mediated signaling by regulating the subcellular location of SMAD2 and SMAD3 and modulating the transcriptional activity of the SMAD3/SMAD4 complex. Possibly associated with TGF-beta receptor internalization.SUBUNIT Interacts (via the SBD region) with SMAD2; the interaction recruits SMAD2 to the TGF-beta receptor and is disrupted by phosphorylation of SMAD2 upon TGF-beta receptor activation. Interacts with SMAD3. Interacts with TGFBR1 and TGFBR2; the interaction recruits SMAD2 to the TGF-beta receptor. Interacts with PML.TISSUE SPECIFICITY Ubiquitous. In the brain found primarily in the cerebrovascular smooth muscle cells and reactive astrocytes.DOMAIN The SMAD binding domain (SBD) interacts with the MH2 domains of SMAD2 or SMAD3.DOMAIN The FYVE-type zinc finger is necessary and sufficient for its localization into early endosomes and mediates the association with PI3P.

UniProtO95405-1

EQUAL

1425

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171172

SMAD2/3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySMAD3 [cytosol]SMAD2 [cytosol]

UniProtP84022UniProtQ15796

Reactome DB_ID: 171266

TGFB1:p-TGFBR:ZFYVE9:SMAD2/3 [early endosome membrane]

TGFB1:p-TGFBR:ZFYVE9:SMAD2/3

TGFB1:TGFBR2:p-5S-T185-TGFBR1:SARA:SMAD2/3TGFB1:p-TGFBR:SARA:SMAD2/3TGF-beta 1:type II receptor:Phospho-type I receptor:SARA:R-SMAD complex

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Reactome DB_ID: 206180

EQUAL

1425

EQUAL

Reactome DB_ID: 170863

Converted from EntitySet in Reactome

Reactome DB_ID: 171172

Reactome Database ID Release 75171266Database 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=171266ReactomeR-HSA-171266

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-171266.1Reactome Database ID Release 75170835Database 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=170835ReactomeR-HSA-170835

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-170835.39865696Pubmed1998SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptorTsukazaki, TChiang, TADavison, AFAttisano, LWrana, JLCell 95:779-91

2.7.11.30

Activated type I receptor phosphorylates SMAD2/3 directly

Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD1, SMAD5 or SMAD8. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-01-18 10:19:52

Reactome DB_ID: 171266

Reactome DB_ID: 113592

Reactome DB_ID: 29370

Reactome DB_ID: 171180

TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3 [early endosome membrane]

TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3

TGFB1:TGFBR2:p-5S-T185-TGFBR1:SARA:p-S465/423,467/425-SMAD2/3TGFB1:p-TGFBR:SARA:p-2S-SMAD2/3TGF-beta 1:type II receptor:Phospho-type I receptor:SARA:Phospho-R-SMAD complexTGFB1:p-TGFBR:SARA:p-S465/423,467/425-SMAD2/3

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

p-2S-SMAD2/3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S465,S467-SMAD2 [cytosol]p-S423,S425-SMAD3 [cytosol]

Reactome DB_ID: 206180

EQUAL

1425

EQUAL

Reactome DB_ID: 170863

Reactome Database ID Release 75171180Database 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=171180ReactomeR-HSA-171180

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-171180.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 171266

GO0004675

GO molecular function

Reactome Database ID Release 75171178Database 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=171178Reactome Database ID Release 75170868Database 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=170868ReactomeR-HSA-170868

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-170868.111100470Pubmed2001Phosphorylation of Smad signaling proteins by receptor serine/threonine kinasesSouchelnytskyi, SRönnstrand, LarsHeldin, Carl-Henrikten Dijke, PMethods Mol Biol 124:107-20

Phosphorylated SMAD2/3 dissociates from TGFBR

Upon phosphorylation of the R-SMAD (SMAD2/3), the conformation of the C-terminal (MH2) domain of the R-SMAD changes, lowering its affinity for the type I receptor and ZFYVE9 (SARA). As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR).

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-01-18 10:19:52

Reactome DB_ID: 171180

Reactome DB_ID: 171173

TGFB1:p-TGFBR:ZFYVE9 [early endosome membrane]

TGFB1:p-TGFBR:ZFYVE9

TGFB1:TGFBR2:p-5S-T185-TGBR1:SARATGF-beta 1:type II receptor:Phospho-type I receptor:SARA complexTGFB1:p-TGFBR:SARA

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Reactome DB_ID: 206180

EQUAL

1425

EQUAL

Reactome DB_ID: 170863

Reactome Database ID Release 75171173Database 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=171173ReactomeR-HSA-171173

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-171173.1Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome Database ID Release 75170850Database 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=170850ReactomeR-HSA-170850

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-170850.19346966Pubmed1997Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signalingSouchelnytskyi, STamaki, KEngstrom, UWernstedt, Cten Dijke, PHeldin, Carl-HenrikJ Biol Chem 272:28107-158980228Pubmed1996MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signalingMacias-Silva, MAbdollah, SHoodless, PAPirone, RAttisano, LWrana, JLCell 87:1215-2415350224Pubmed2004Structural basis of heteromeric smad protein assembly in TGF-beta signalingChacko, BMQin, BYTiwari, AShi, GLam, SHayward, LJDe Caestecker, MLin, KMol Cell 15:813-239311995Pubmed1997TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4Nakao, ASouchelnytskyi, SKawabata, MIshisaki, AOeda, ETamaki, KHanai, JHeldin, Carl-HenrikMiyazono, Kten Dijke, PEMBO J 16:5353-62

Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4

The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif. ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).

Reactome DB_ID: 170862

UniProt:Q13485 SMAD4

SMAD4

SMAD4MADH4DPC4FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Found in a complex with SMAD1 and YY1 (By similarity). Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3 (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.

UniProtQ13485

EQUAL

552

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome DB_ID: 171175

p-2S-SMAD2/3:SMAD4 [cytosol]

p-2S-SMAD2/3:SMAD4

Phospho-R-SMAD:CO-SMAD complex

Reactome DB_ID: 170862

EQUAL

552

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome Database ID Release 75171175Database 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=171175ReactomeR-HSA-171175

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-171175.1Reactome Database ID Release 75170847Database 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=170847ReactomeR-HSA-170847

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-170847.39670020Pubmed1998Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptorsKawabata, MInoue, HHanyu, AImamura, TMiyazono, KEMBO J 17:4056-6511779503Pubmed2001Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.Wu, JWHu, MChai, JSeoane, JHuse, MLi, CRigotti, DJKyin, SMuir, TWFairman, RMassague, JShi, YMol Cell 8:1277-8917272273Pubmed2007Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signalingChen, Ye-GuangWang, ZhiMa, JingZhang, LongLu, ZhongxianJ. Biol. Chem. 282:9688-9511779505Pubmed2001Structural basis of Smad1 activation by receptor kinase phosphorylationQin, BYChacko, BMLam, SSde Caestecker, MPCorreia, JJLin, KMol Cell 8:1303-12

Downregulation of TGF-beta receptor signaling

TGF-beta receptor signaling is downregulated by proteasome and lysosome-mediated degradation of ubiquitinated TGFBR1, SMAD2 and SMAD3, as well as by dephosphorylation of TGFBR1, SMAD2 and SMAD3. In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Binding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultaneously binds SMAD7 and TGFBR1 (Datta et al. 2000). BAMBI simultaneously binds SMAD7 and activated TGFBR1, leading to downregulation of TGF-beta receptor complex signaling (Onichtchouk et al. 1999, Yan et al. 2009). In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004). SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012). Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1)

I-SMADs (SMAD6 and SMAD7) reside in the nucleus presumably to be sequestered from the TGF-beta receptor complex and thus avoid inappropriate silencing of the signaling pathway. Upon activation of the signaling pathway, I-SMADs exit the nucleus and are recruited to the signaling TGF-beta receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-02-10 14:02:35Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173478

UniProt:O15105 SMAD7

SMAD7

MADH7MADH8SMAD7FUNCTION Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with PDPK1 (via PH domain).TISSUE SPECIFICITY Ubiquitous with higher expression in the lung and vascular endothelium.INDUCTION By TGFB1.PTM Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1.PTM Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251).PTM Acetylation prevents ubiquitination and degradation mediated by SMURF1.SIMILARITY Belongs to the dwarfin/SMAD family.

UniProtO15105

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Reactome DB_ID: 170841

Reactome DB_ID: 173476

TGFB1: p-TGFBR: I-SMAD7 [plasma membrane]

TGFB1: p-TGFBR: I-SMAD7

TGFB1:TGFBR2:p-5S-T185-TGFBR1:I-SMAD7TGF-beta 1:type II receptor:Phospho-type I receptor:I-SMAD7 complex

Reactome DB_ID: 173478

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Reactome DB_ID: 170841

Reactome Database ID Release 75173476Database 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=173476ReactomeR-HSA-173476

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-173476.2Reactome Database ID Release 75173512Database 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=173512ReactomeR-HSA-173512

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-173512.29215638Pubmed1997The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signalingHayashi, HAbdollah, SQiu, YCai, JXu, YYGrinnell, BWRichardson, MATopper, JNGimbrone MA, JrWrana, JLFalb, DCell 89:1165-739335507Pubmed1997Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signallingNakao, AAfrakhte, MMoren, ANakayama, TChristian, JLHeuchel, RItoh, SKawabata, MHeldin, NEHeldin, Carl-Henrikten Dijke, PNature 389:631-5GO0030512

GO biological process

STRAP binds phosphorylated TGF-beta receptor complex

STRAP (serine-threonine kinase receptor-associated protein) binds to the activated TGF-beta receptor complex. In in vitro studies, STRAP is able to bind both TGFBR1 and TGFBR2 (Datta et al. 1998). This was deduced from experiments in which a recombinant mouse Strap and recombinant human TGFBR1 and TGFBR2 were expressed in COS1 cells. STRAP is also able to bind unphosphorylated TGF-beta receptor complex, but the physiological significance, if any, of this interaction is not known.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 170841

Reactome DB_ID: 2127556

UniProt:Q9Y3F4 STRAP

STRAP

MAWDUNRIPSTRAPFUNCTION The SMN complex plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Thereby, plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP. In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. Dissociation by the SMN complex of CLNS1A from the trapped Sm proteins and their transfer to an SMN-Sm complex triggers the assembly of core snRNPs and their transport to the nucleus. STRAP plays a role in the cellular distribution of the SMN complex. Negatively regulates TGF-beta signaling but positively regulates the PDPK1 kinase activity by enhancing its autophosphorylation and by significantly reducing the association of PDPK1 with 14-3-3 protein.SUBUNIT Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG. Interacts directly with GEMIN6 and GEMIN7. Associates with the SMN complex in the cytoplasm but not in the nucleus. Also interacts with CSDE1/UNR and MAWBP. Interacts with PDPK1. Interacts with PRMT5; facilitates the interaction between PRMT5 and TP53 (PubMed:19011621).SIMILARITY Belongs to the WD repeat STRAP family.

UniProtQ9Y3F4

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350

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Reactome DB_ID: 2127564

TGFB1:p-TGFBR:STRAP [plasma membrane]

TGFB1:p-TGFBR:STRAP

Reactome DB_ID: 170841

Reactome DB_ID: 2127556

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Reactome Database ID Release 752127564Database 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=2127564ReactomeR-HSA-2127564

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-2127564.1Reactome Database ID Release 752127562Database 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=2127562ReactomeR-HSA-2127562

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-2127562.19856985Pubmed1998Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signalingDatta, PKChytil, AGorska, AEMoses, HLJ Biol Chem 273:34671-4

STRAP stabilizes interaction of activated TGF-beta receptor complex with SMAD7

STRAP binds both TGF-beta receptor and SMAD7, and stabilizes interaction of phosphorylated TGF-beta receptor complex with SMAD7.This reaction may involve oligomerization of STRAP. STRAP and SMAD7 act synergistically to inhibit the transcription of TGF-beta target genes by preventing SMAD2 and SMAD3 from binding phosphorylated TGFBR1.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173478

EQUAL

426

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Reactome DB_ID: 2127564

Reactome DB_ID: 2128993

TGFB1: p-TGFBR: STRAP: SMAD7 [plasma membrane]

TGFB1: p-TGFBR: STRAP: SMAD7

Reactome DB_ID: 173478

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426

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Reactome DB_ID: 2127564

Reactome Database ID Release 752128993Database 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=2128993ReactomeR-HSA-2128993

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-2128993.1Reactome Database ID Release 752128994Database 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=2128994ReactomeR-HSA-2128994

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-2128994.110757800Pubmed2000STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signalingDatta, PKMoses, HLMol Cell Biol 20:3157-67

BAMBI interferes with the interaction of type I receptor with type II receptor

BAMBI (BMP and activin membrane-bound inhibitor) is a transmembrane protein closely related to TGF-beta family receptors type I, but without serine/threonine kinase activity. In Xenopus, BAMBI expression is regulated by BMP4. BAMBI interferes with BMP, activin and TGF-beta receptor complex signaling. BAMBI binds various TGF-beta type I receptors, showing the highest affinity for TGFBR1. BAMBI can also bind TGFBR2 and activin receptor type II (Onichtchouk et al. 1999). BAMBI binds SMAD7, and this interaction involves MH1 and MH2 domains of SMAD7 and the intracellular domain of BAMBI. BAMBI and SMAD7 cooperate in the repression of TGF-beta receptor complex signaling, but BAMBI-mediated recruitment of SMAD7 to activated TGF-beta receptor complex, as BAMBI preferentially binds activated TGFBR1, does not lead to TGFBR1 degradation (Yan et al. 2009). BAMBI may downregulate TGF-beta receptor complex signaling by replacing one TGFBR1 molecule in the TGF-beta receptor heterotetramer (Onichtchouk et al. 1999). Alternatively, BAMBI-mediated recruitment of SMAD7 may compete with binding of SMAD2 and SMAD3 (R-SMADs) to the activated TGF-beta receptor complex, thus interfering with the activation of R-SMADs (Yan et al. 2009).

Authored: Jassal, B, 2006-02-10 14:02:35Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2006-02-10 14:02:35

Reactome DB_ID: 173478

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Reactome DB_ID: 170841

Reactome DB_ID: 173484

UniProt:Q13145 BAMBI

BAMBI

NMABAMBIFUNCTION Negatively regulates TGF-beta signaling.TISSUE SPECIFICITY High expression in kidney medulla, placenta and spleen; low in kidney cortex, liver, prostate and gut. Not expressed in normal skin, expression is high in melanocytes and in 3 out of 11 melanoma metastases tested.DEVELOPMENTAL STAGE Expression in poorly metastatic human melanoma cell lines; no expression in highly metastatic human melanoma cell lines.SIMILARITY Belongs to the BAMBI family.

UniProtQ13145

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Reactome DB_ID: 173509

TGFB1: TGFBR2: p-TGFBR1: BAMBI: SMAD7 [plasma membrane]

TGFB1: TGFBR2: p-TGFBR1: BAMBI: SMAD7

Reactome DB_ID: 173478

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Reactome DB_ID: 170841

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Reactome Database ID Release 75173509Database 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=173509ReactomeR-HSA-173509

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-173509.1Reactome Database ID Release 75173483Database 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=173483ReactomeR-HSA-173483

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-173483.210519551Pubmed1999Silencing of TGF-beta signalling by the pseudoreceptor BAMBIOnichtchouk, DChen, Y GDosch, RGawantka, VDelius, HMassagué, JNiehrs, CNature 401:480-519758997Pubmed2009Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signalingYan, XLin, ZChen, FZhao, XChen, HNing, YChen, YGJ Biol Chem 284:30097-104

SMAD7 recruits GADD34:PP1 to phosphorylated TGFBR

SMAD7 recruits protein phosphatase 1 (PP1) to TGF-beta receptor complex by binding to the PP1 regulatory subunit PPP1R15A (GADD34). ZFYVE9 (SARA) stabilizes the complex by directly interacting with PP1 catalytic subunit, and presumably TGF-beta receptor complex (Shi et al. 2004). This was deduced based on experiments involving recombinant mouse Smad7 and recombinant human PPP1R15A, TGFBR1, TGFBR2 and SARA.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2162158

GADD34:PP1 [cytosol]

GADD34:PP1

Converted from EntitySet in Reactome

Reactome DB_ID: 163538

PP1 catalytic subunit [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPPP1CB [cytosol]PPP1CA [cytosol]PPP1CC [cytosol]

UniProtP62140UniProtP62136UniProtP36873

Reactome DB_ID: 178231

UniProt:O75807 PPP1R15A

PPP1R15A

PPP1R15AGADD34FUNCTION Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.SUBUNIT Interacts with PCNA (By similarity). Interacts with LYN and KMT2A/MLL1. Interacts with PP1, PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1.INDUCTION Specifically produced in response to stress: in absence of stress, some upstream open reading frame (uORF) of this transcript is translated, thereby preventing its translation (PubMed:19131336). By methyl methanesulfonate and ionizing irradiation (PubMed:9153226). By IL24/interleukin-24 in melanoma cells; which induces apoptosis (PubMed:10490642, PubMed:12114539).PTM Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-262 enhances proteasomal degradation, this position is dephosphorylated by PTPN2.PTM Polyubiquitinated. Exhibits a rapid proteasomal degradation with a half-life under 1 hour, ubiquitination depends on endoplasmic reticulum association.MISCELLANEOUS The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SIMILARITY Belongs to the PPP1R15 family.

UniProtO75807

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674

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Reactome Database ID Release 752162158Database 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=2162158ReactomeR-HSA-2162158

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-2162158.1

Reactome DB_ID: 173476

Reactome DB_ID: 206180

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Reactome DB_ID: 2167884

TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9 [early endosome membrane]

TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9

TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA

Reactome DB_ID: 2162158

Reactome DB_ID: 173476

Reactome DB_ID: 206180

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Reactome Database ID Release 752167884Database 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=2167884ReactomeR-HSA-2167884

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-2167884.1Reactome Database ID Release 75178189Database 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=178189ReactomeR-HSA-178189

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-178189.114718519Pubmed2004GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptorShi, WSun, CHe, BXiong, WShi, XYao, DCao, XJ Cell Biol 164:291-300

3.1.3.16

PP1 dephosphorylates TGFBR1

PP1 dephosphorylates TGF-beta receptor-1 (TGFBR1), thereby inhibiting TGF-beta signaling. It has not been precisely examined whether PP1 dephosphorylates all TGFBR1 serine and threonine residues phosphorylated by TGFBR2 (Shi et al. 2004). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human TGFBR1, TGFBR2 and PP1.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2167884

Reactome DB_ID: 29356

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 173478

EQUAL

426

EQUAL

Reactome DB_ID: 2162158

Reactome DB_ID: 206180

EQUAL

1425

EQUAL

Reactome DB_ID: 29372

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

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

ChEBI43474

Reactome DB_ID: 2167873

TGFB1:TGFBR2:TGFBR1 [early endosome membrane]

TGFB1:TGFBR2:TGFBR1

TGF-beta 1:type II receptor:type I receptor complex

Reactome DB_ID: 170866

Reactome DB_ID: 170852

Reactome DB_ID: 170864

Reactome Database ID Release 752167873Database 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=2167873ReactomeR-HSA-2167873

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-2167873.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2167884

GO0004721

GO molecular function

Reactome Database ID Release 75178169Database 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=178169Reactome Database ID Release 75178178Database 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=178178ReactomeR-HSA-178178

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-178178.2

SMAD7 binds to SMURF2

SMURF2, an E3 ubiquitin protein ligase, binds to SMAD7 in the nucleus. WW2 and WW3 domains of SMURF2 are both required for binding PY motif (PPXY sequence) of SMAD7. Endogenous human SMAD7 and SMURF2 were shown to form a complex in human U4A/Jak1 cells, derived from a sarcoma cell line 2fTGH. The interaction was studied in more detail by expressing tagged recombinant human SMURF2 and mouse Smad7 in human embryonic kidney cell line HEK293 (Kavsak et al. 2000, Ogunjimi et al. 2005).

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 178197

nucleoplasmGO0005654

EQUAL

426

EQUAL

Reactome DB_ID: 178202

UniProt:Q9HAU4 SMURF2

SMURF2

SMURF2FUNCTION E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1. Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3. In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation. Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2. Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level. Negatively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation (PubMed:30696809).ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts (via WW domains) with SMAD1. Interacts (via WW domains) with SMAD2 (via PY-motif). Interacts (via WW domains) with SMAD3 (via PY-motif). Interacts with SMAD6. Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation. Does not interact with SMAD4; SMAD4 lacks a PY-motif. Interacts with AIMP1. Interacts with STAMBP and RNF11. Interacts with NDFIP1 and NDFIP2 (Probable); this interaction activates the E3 ubiquitin-protein ligase. Interacts with TTC3 (PubMed:30696809).TISSUE SPECIFICITY Widely expressed.DOMAIN The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).DOMAIN The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.PTM Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome (PubMed:21572392, PubMed:30696809).

UniProtQ9HAU4

EQUAL

748

EQUAL

Reactome DB_ID: 2167870

SMAD7:SMURF2 [nucleoplasm]

SMAD7:SMURF2

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 178202

EQUAL

748

EQUAL

Reactome Database ID Release 752167870Database 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=2167870ReactomeR-HSA-2167870

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-2167870.1Reactome Database ID Release 75178208Database 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=178208ReactomeR-HSA-178208

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-178208.111163210Pubmed2000Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradationKavsak, PRasmussen, RKCausing, CGBonni, SZhu, HThomsen, GHWrana, JLMol Cell 6:1365-7516061177Pubmed2005Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domainOgunjimi, AABriant, DJPece-Barbara, NLe Roy, CDi Guglielmo, GMKavsak, PRasmussen, RKSeet, BTSicheri, FWrana, JLMol Cell 19:297-308

SMAD7:SMURF2 complex translocates to the cytosol

After forming a complex in the nucleus, SMAD7:SMURF2 traffics to the cytosol (Kavsak et al. 2000). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human SMURF2.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2167870

Reactome DB_ID: 2167883

SMAD7:SMURF2 [cytosol]

SMAD7:SMURF2

Reactome DB_ID: 173478

EQUAL

426

EQUAL

Reactome DB_ID: 173537

EQUAL

748

EQUAL

Reactome Database ID Release 752167883Database 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=2167883ReactomeR-HSA-2167883

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-2167883.2Reactome Database ID Release 752167876Database 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=2167876ReactomeR-HSA-2167876

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-2167876.1

SMAD7 binds to SMURF1

SMAD7 binds to SMURF1 in the nucleus (Ebisawa et al. 2001, Tajima et al. 2003). SMURF1 domains WW1 and WW2, highly similar to WW2 and WW3 domains of SMURF2, are involved in SMAD7 binding. SMURF1 has two splicing isoforms. The shorter splicing isoform of SMURF1 has an inter-WW domain linker of the same length as the WW2-WW3 domain linker of SMURF2. The longer isoform of SMURF1 has a longer WW1-WW2 domain linker, resulting in decreased affinity of the longer SMURF1 isoform for SMAD7 (Chong et al. 2010). This is based on experiments with recombinant mouse Smad7 and recombinant human SMURF1.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 3004548

UniProt:Q9HCE7 SMURF1

SMURF1

KIAA1625SMURF1FUNCTION E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA. Promotes ubiquitination and subsequent proteasomal degradation of MAVS (PubMed:23087404). Plays a role in dendrite formation by melanocytes (PubMed:23999003).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with TRAF4. Interacts (via HECT domain) with FBXL15 (via LRR repeats). Interacts with SMAD7 and TGFBR1; SMAD7 recruits SMURF1 to TGFBR1 and regulates TGF-beta receptor degradation. Interacts with MAVS; the interaction is mediated by NDFIP1 (PubMed:23087404).TISSUE SPECIFICITY Expressed in melanocytes (PubMed:23999003).DOMAIN The C2 domain mediates membrane localization and substrate selection.PTM Auto-ubiquitinated in presence of NDFIP1 (PubMed:23087404). Ubiquitinated by the SCF(FBXL15) complex at Lys-381 and Lys-383, leading to its degradation by the proteasome. Lys-383 is the primary ubiquitination site.

UniProtQ9HCE7

EQUAL

757

EQUAL

Reactome DB_ID: 2167913

SMAD7:SMURF1 [nucleoplasm]

SMAD7:SMURF1

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 3004548

EQUAL

757

EQUAL

Reactome Database ID Release 752167913Database 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=2167913ReactomeR-HSA-2167913

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-2167913.1Reactome Database ID Release 752167917Database 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=2167917ReactomeR-HSA-2167917

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-2167917.112519765Pubmed2003Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7Tajima, YGoto, KYoshida, MShinomiya, KSekimoto, TYoneda, YMiyazono, KImamura, TJ Biol Chem 278:10716-2120937913Pubmed2010Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificityChong, PALin, HWrana, JLForman-Kay, JDProc Natl Acad Sci U S A 107:18404-911278251Pubmed2001Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradationEbisawa, TFukuchi, MMurakami, GChiba, TTanaka, KImamura, TMiyazono, KJ Biol Chem 276:12477-80

SMAD7:SMURF1 complex binds XPO1 (CRM1)

SMAD7:SMURF1 complex binds to XPO1 (CRM1) through a nuclear export signal (NES) located in the C-terminus of SMURF1 (Tajima et al. 2003). Recombinant mouse Smad7 and recombinant human SMURF1 were used in this study.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2167913

Reactome DB_ID: 165529

UniProt:O14980 XPO1

XPO1

XPO1CRM1FUNCTION Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap.FUNCTION (Microbial infection) Mediates the export of unspliced or incompletely spliced RNAs out of the nucleus from different viruses including HIV-1, HTLV-1 and influenza A. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.SUBUNIT Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA (By similarity). Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1. Found in a trimeric export complex with SNUPN, RAN and XPO1. Found in a nuclear export complex with RANBP3 and RAN. Found in a 60S ribosomal subunit export complex with NMD3, RAN, XPO1. Interacts with DDX3X, NMD3, NUP42, NUP88, NUP214, RANBP3 and TERT. Interacts with NEMF (via its N-terminus). Interacts with the monomeric form of BIRC5/survivin deacetylated at 'Lys-129'. Interacts with DTNBP1 and SERTAD2; the interactions translocate DTNBP1 and SERTAD2 out of the nucleus. Interacts with ATF2. Interacts with SLC35G1 and STIM1. Interacts with DCAF8. Interacts with CPEB3 (PubMed:22730302). Interacts with HAX1 (PubMed:23164465). Interacts with BOK; translocates to the cytoplasm (PubMed:16302269). Interacts with HSP90AB1 (PubMed:22022502).SUBUNIT (Microbial infection) Interacts with HIV-1 Rev.SUBUNIT (Microbial infection) Interacts with HTLV-1 Rex.SUBUNIT (Microbial infection) Interacts with influenza A nucleoprotein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein BMLF1.SUBUNIT (Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.SUBUNIT (Microbial infection) Interacts with SARS-CoV virus protein ORF9b; this interaction mediates protein ORF9b export out of the nucleus.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Not expressed in the kidney.MISCELLANEOUS Cellular target of leptomycin B (LMB), a XPO1/CRM1 nuclear export inhibitor.SIMILARITY Belongs to the exportin family.

UniProtO14980

EQUAL

1071

EQUAL

Reactome DB_ID: 2167923

SMAD7:SMURF1:XPO1 [nucleoplasm]

SMAD7:SMURF1:XPO1

Reactome DB_ID: 2167913

Reactome DB_ID: 165529

EQUAL

1071

EQUAL

Reactome Database ID Release 752167923Database 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=2167923ReactomeR-HSA-2167923

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-2167923.1Reactome Database ID Release 752167924Database 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=2167924ReactomeR-HSA-2167924

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-2167924.1

SMAD7:SMURF1 complex is exported to the cytosol

After SMAD7:SMURF1 complex binds to XPO1 (CRM1) through the nuclear export signal (NES) in the C-terminus of SMURF1, XPO1 enables transport of SMAD7:SMURF1 to the cytosol (Suzuki et al. 2002, Tajima et al. 2003). A recombinant mouse Smad7 and recombinant human SMURF1 were used in these experiments.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2167923

Reactome DB_ID: 165539

EQUAL

1071

EQUAL

Reactome DB_ID: 2167927

SMAD7:SMURF1 [cytosol]

SMAD7:SMURF1

Reactome DB_ID: 173478

EQUAL

426

EQUAL

Reactome DB_ID: 975972

EQUAL

757

EQUAL

Reactome Database ID Release 752167927Database 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=2167927ReactomeR-HSA-2167927

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-2167927.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2167923

GO0005215

GO molecular function

Reactome Database ID Release 75178174Database 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=178174Reactome Database ID Release 75178215Database 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=178215ReactomeR-HSA-178215

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-178215.112151385Pubmed2002Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membraneSuzuki, CMurakami, GFukuchi, MShimanuki, TShikauchi, YImamura, TMiyazono, KJ Biol Chem 277:39919-25

NEDD4L ubiquitin ligase binds SMAD7

NEDD4L ubiquitin ligase, structurally similar to SMURF ubiquitin ligases, binds SMAD7 (Kuratomi et al. 2005). This was inferred from experiments that used recombinant mouse Smad7 and recombinant human NEDD4L.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176420

UniProt:Q96PU5 NEDD4L

NEDD4L

NEDD4LKIAA0439NEDL3FUNCTION E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338). Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Plays a role in dendrite formation by melanocytes (PubMed:23999003). Involved in the regulation of TOR signaling (PubMed:27694961). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338).ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with UBE2E3 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:26363003, PubMed:11748237). Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5 (PubMed:11696533, PubMed:14556380, PubMed:15217910, PubMed:15489223, PubMed:15548568). Interacts with SMAD2, SMAD3, SMAD6 and SMAD7 (PubMed:15496141). The phosphorylated form interacts with 14-3-3 proteins (PubMed:15677482). Interacts with TNK2 (PubMed:19144635, PubMed:20086093). Interacts with WNK1 (PubMed:20525693). Interacts with SGK1 (PubMed:11696533, PubMed:20730100). Interacts (via C2 domain) with NPC2 (PubMed:19664597). Interacts with ARRDC4 (PubMed:23236378). Interacts with KCNQ1; promotes internalization of KCNQ1 (PubMed:22024150). Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus LMP2A.TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in prostate, pancreas and kidney (PubMed:14615060, PubMed:15496141, PubMed:19664597). Expressed in melanocytes (PubMed:23999003).INDUCTION By androgens in prostate, and by albumin in kidney.PTM Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation.PTM Auto-ubiquitinated (PubMed:19343052). Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other's ubiquitination levels (PubMed:27445338).

UniProtQ96PU5

EQUAL

975

EQUAL

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 2176418

SMAD7:NEDD4L [nucleoplasm]

SMAD7:NEDD4L

Reactome DB_ID: 2176420

EQUAL

975

EQUAL

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome Database ID Release 752176418Database 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=2176418ReactomeR-HSA-2176418

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-2176418.1Reactome Database ID Release 752176416Database 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=2176416ReactomeR-HSA-2176416

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-2176416.115496141Pubmed2005NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptorKuratomi, GKomuro, AGoto, KShinozaki, MMiyazawa, KMiyazono, KImamura, TBiochem J 386:461-70

SMAD7:NEDD4L complex translocates to the cytosol

Binding of NEDD4L promotes translocation of SMAD7 to the cytosol (Kuratomi et al. 2005). This is based on experiments using recombinant mouse Smad7 and recombinant human NEDD4L.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176418

Reactome DB_ID: 2176419

SMAD7:NEDD4L [cytosol]

SMAD7:NEDD4L

Reactome DB_ID: 173478

EQUAL

426

EQUAL

Reactome DB_ID: 976003

EQUAL

975

EQUAL

Reactome Database ID Release 752176419Database 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=2176419ReactomeR-HSA-2176419

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-2176419.1Reactome Database ID Release 752176417Database 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=2176417ReactomeR-HSA-2176417

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-2176417.1

SMAD7:SMURF complex binds to phosphorylated TGFBR1

SMAD7 binds to phosphorylated TGFBR1 (TGF-beta receptor I), thereby recruiting SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases to the activated TGF-beta receptor complex. This is based on experiments in which recombinant mouse Smad7 was used together with recombinant human ubiquitin ligases and TGF-beta receptors.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2169026

SMAD7:SMURF/NEDD4L [cytosol]

SMAD7:SMURF/NEDD4L

Reactome DB_ID: 173478

EQUAL

426

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2176415

SMURF/NEDD4L [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNEDD4L [cytosol]SMURF2 [cytosol]SMURF1 [cytosol]

Reactome Database ID Release 752169026Database 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=2169026ReactomeR-HSA-2169026

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-2169026.1

Reactome DB_ID: 170841

Reactome DB_ID: 2169025

TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L [plasma membrane]

TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L

Reactome DB_ID: 2169026

Reactome DB_ID: 170841

Reactome Database ID Release 752169025Database 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=2169025ReactomeR-HSA-2169025

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-2169025.1Reactome Database ID Release 75178218Database 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=178218ReactomeR-HSA-178218

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-178218.1

6.3.2.19

SMURFs/NEDD4L ubiquitinate phosphorylated TGFBR1 and SMAD7

SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases, recruited to TGF-beta receptor complex through interaction with SMAD7, ubiquitinate both SMAD7 and/or TGF-beta receptor I (TGFBR1), targeting the complex for degradation. This was inferred from experiments using a recombinant mouse Smad7 with recombinant human ubiquitin ligases and TGF-beta receptors.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

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: 2169025

Converted from EntitySet in Reactome

Reactome DB_ID: 2176415

Reactome DB_ID: 2169047

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 [plasma membrane]

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7

Reactome DB_ID: 173476

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752169047Database 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=2169047ReactomeR-HSA-2169047

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-2169047.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2169025

GO0004842

GO molecular function

Reactome Database ID Release 752169049Database 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=2169049Reactome Database ID Release 752169050Database 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=2169050ReactomeR-HSA-2169050

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-2169050.1

Degradation of TGF-beta receptor complex

Recruitment of SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) to the activated TGF-beta receptor complex by SMAD7 and subsequent ubiquitination of SMAD7 and/or TGFBR1 triggers degradation of SMAD7 and TGFBR1 through proteasome and lysosome-dependent routes, resulting in downregulation of signaling by TGF-beta receptors.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2169047

Reactome Database ID Release 752169046Database 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=2169046ReactomeR-HSA-2169046

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-2169046.1

UCHL5 binds SMAD7 in complex with ubiquitinated TGFBR1

Ubiquitin C-terminal hydrolase UCHL5 (UCH37) strongly binds to SMAD7 and is thereby recruited to TGF-beta receptor complex (Wicks et al. 2005). Another ubiquitin peptidase, USP15, has recently been found to associate with ubiquitinated TGFBR1 through SMAD7 (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments with human proteins.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2169047

Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

UCHL5/USP15 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP15 [cytosol]UCHL5 [cytosol]

UniProtQ9Y4E8UniProtQ9Y5K5

Reactome DB_ID: 2179287

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 [plasma membrane]

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15

Reactome DB_ID: 2169047

Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

Reactome Database ID Release 752179287Database 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=2179287ReactomeR-HSA-2179287

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-2179287.1Reactome Database ID Release 752179293Database 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=2179293ReactomeR-HSA-2179293

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-2179293.122344298Pubmed2012USP15 stabilizes TGF-? receptor I and promotes oncogenesis through the activation of TGF-? signaling in glioblastomaEichhorn, PJRodón, LGonzàlez-Juncà, ADirac, AGili, MMartínez-Sáez, EAura, CBarba, IPeg, VPrat, ACuartas, IJimenez, JGarcía-Dorado, DSahuquillo, JBernards, RBaselga, JSeoane, JNat Med 18:429-3516027725Pubmed2005The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signallingWicks, SJHaros, KMaillard, MSong, LCohen, REDijke, PTChantry, AOncogene 24:8080-4

UCHL5, USP15 deubiquitinate TGFBR1

Ubiquitin C-terminal hydrolase UCHL5 (UCH37) deubiquitinates TGFBR1, stabilizing TGF-beta receptor complex and prolonging TGF-beta receptor signaling. Deubiqutination of SMAD7 by UCHL5 has not been examined in this context (Wicks et al. 2005). Ubiquitin peptidase USP15 also deubiquitinates and stabilizes TGFBR1, leading to enhanced signaling by TGF-beta receptor complex. USP15 does not affect the ubiquitination status of SMAD7. Amplification of USP15 has recently been reported in glioblastoma, breast and ovarian cancer. In advanced glioblastoma, TGF-beta receptor signaling acts as an oncogenic factor, and USP15-mediated upregulation of TGF-beta receptor signaling may be a key factor in glioblastoma pathogenesis (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments using human proteins.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2179287

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 2179328

TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7 [plasma membrane]

TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7

Reactome DB_ID: 173476

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752179328Database 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=2179328ReactomeR-HSA-2179328

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-2179328.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2179287

GO0004843

GO molecular function

Reactome Database ID Release 752179282Database 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=2179282Reactome Database ID Release 752179291Database 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=2179291ReactomeR-HSA-2179291

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-2179291.3

SMURF2 binds SMAD2

SMURF2 binds SMAD2 irrespective of TGF-beta signaling (Zhang et al. 2001).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173537

EQUAL

748

EQUAL

Reactome DB_ID: 3006353

UniProt:Q15796 SMAD2

SMAD2

SMAD2MADH2MADR2FUNCTION Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; the absence of TGF-beta. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4. Interacts with AIP1, HGS, PML and WWP1 (By similarity). Interacts with NEDD4L in response to TGF-beta (By similarity). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta. Interacts with ACVR1B, SMAD3 and TRIM33. Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with FOXH1, homeobox protein TGIF, PEBP2-alpha subunit, CREB-binding protein (CBP), EP300, SKI and SNW1. Interacts with SNON; when phosphorylated at Ser-465/467. Interacts with SKOR1 and SKOR2. Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3. Interacts with RBPMS. Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C. Interacts with ZNF580. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif). Interacts with ZFHX3. Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity).TISSUE SPECIFICITY Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta.PTM Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1.PTM In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity).PTM Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta.SIMILARITY Belongs to the dwarfin/SMAD family.

EQUAL

467

EQUAL

Reactome DB_ID: 2176457

SMAD2:SMURF2 [cytosol]

SMAD2:SMURF2

Reactome DB_ID: 173537

EQUAL

748

EQUAL

Reactome DB_ID: 3006353

EQUAL

467

EQUAL

Reactome Database ID Release 752176457Database 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=2176457ReactomeR-HSA-2176457

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-2176457.1Reactome Database ID Release 752176445Database 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=2176445ReactomeR-HSA-2176445

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-2176445.111158580Pubmed2001Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligaseZhang, YChang, CGehling, DJHemmati-Brivanlou, ADerynck, RProc Natl Acad Sci U S A 98:974-9

6.3.2.19

SMURF2 ubiquitinates SMAD2

SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation.

Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02Reviewed: Heldin, CH, 2006-04-18 14:26:12Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2006-02-14 10:42:31

Reactome DB_ID: 2176457

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 173537

EQUAL

748

EQUAL

Reactome DB_ID: 2176443

Ub-SMAD2 [cytosol]

Ub-SMAD2

Reactome DB_ID: 3006353

EQUAL

467

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752176443Database 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=2176443ReactomeR-HSA-2176443

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-2176443.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2176457

Reactome Database ID Release 752176453Database 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=2176453Reactome Database ID Release 75173542Database 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=173542ReactomeR-HSA-173542

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-173542.1

Degradation of ubiquitinated SMAD2

Ubiquitinated SMAD2 undergoes proteasome-dependent degradation. Therefore, SMURF2 decreases the level of SMAD2 in the cell, irrespective of TGF-beta signaling, and may regulate the competence of a cell to respond to TGF-beta signaling (Zhang et al. 2001). These findings are contradicted by a recent study of Smurf2 knockout mice, where Smad2 protein levels were found to be unaltered in the absence of Smurf2 (Tang et al. 2011).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176443

Reactome Database ID Release 752176452Database 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=2176452ReactomeR-HSA-2176452

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-2176452.122045334Pubmed2011Ablation of Smurf2 reveals an inhibition in TGF-? signalling through multiple mono-ubiquitination of Smad3Tang, LYYamashita, MCoussens, NPTang, YWang, XLi, CDeng, CXCheng, SYZhang, YEEMBO J 30:4777-89

SMAD3 binds STUB1 (CHIP)

STUB1 (CHIP), an E3 ubiquitin ligase, binds SMAD3 irrespective of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 170855

UniProt:P84022 SMAD3

SMAD3

MADH3SMAD3FUNCTION Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, HGS, WWP1 and SNW1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts (via MH2 domain) with ZFYVE9. Interacts with HDAC1, TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and TGFB1I1. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1. Interacts with ZC3H3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ZFHX3. Interacts weakly with ZNF8 (PubMed:12370310). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (By similarity). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (PubMed:24613385). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).SUBUNIT (Microbial infection) Interacts with SARS-CoV nucleoprotein.DOMAIN The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.DOMAIN The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.PTM Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.PTM Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.PTM Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.PTM Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).SIMILARITY Belongs to the dwarfin/SMAD family.

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425

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Reactome DB_ID: 975970

UniProt:Q9UNE7 STUB1

STUB1

CHIPSTUB1PP1131FUNCTION E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation (PubMed:27708256). Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner (PubMed:23973223). Likely mediates polyubiquitination and downregulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385). May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820). Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer (By similarity). Interacts with BAG2 (PubMed:16169850). Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3 (PubMed:11557750). Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (PubMed:15215316). Interacts with MKKS (PubMed:18094050). Interacts with DNAAF4 (PubMed:19423554). Interacts with POLB (PubMed:19713937). Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity). Interacts with DNAJB6 (PubMed:22366786). Interacts with FOXP3 (PubMed:23973223). Interacts with FLCN (PubMed:27353360). Interacts with HSP90AA1 (PubMed:27353360, PubMed:24613385). Interacts with HSP90 (PubMed:11146632). Interacts with UBE2N and UBE2V1 (PubMed:16307917). Interacts (via TPR repeats) with the C-terminal domain of HSPA1A (PubMed:10330192). Interacts with the non-acetylated form of HSPA1A and HSPA1B (PubMed:27708256). Interacts (via TPR repeats) with the C-terminal domain of HSPA8 (PubMed:10330192, PubMed:11557750, PubMed:23990462, PubMed:27708256). Interacts with SMAD3 and HSP90AB1 (PubMed:24613385). Interacts with UBE4B (PubMed:17369820). Interacts with RIPK3 (PubMed:29883609).TISSUE SPECIFICITY Expressed in differentiated myotubes (at protein level) (PubMed:17369820). Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (PubMed:10330192, PubMed:11435423). Detected in kidney, liver and lung (PubMed:10330192, PubMed:11435423).INDUCTION Up-regulated by inflammatory signals in regulatory T-cells (Treg).DOMAIN The U-box domain is required for the ubiquitin protein ligase activity.DOMAIN The TPR domain is essential for ubiquitination mediated by UBE2D1.PTM Monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3 (By similarity). Auto-ubiquitinated; mediated by UBE2D1 and UBE2D2.MISCELLANEOUS Antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) and in colorectal cancer patients.

UniProtQ9UNE7

EQUAL

303

EQUAL

Reactome DB_ID: 2187365

SMAD3:STUB1 [cytosol]

SMAD3:STUB1

Reactome DB_ID: 170855

EQUAL

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Reactome DB_ID: 975970

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EQUAL

Reactome Database ID Release 752187365Database 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=2187365ReactomeR-HSA-2187365

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-2187365.1Reactome Database ID Release 752187375Database 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=2187375ReactomeR-HSA-2187375

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-2187375.114701756Pubmed2004CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcriptionLi, LXin, HXu, XHuang, MZhang, XChen, YZhang, SFu, XYChang, ZMol Cell Biol 24:856-6415781469Pubmed2005CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradationXin, HXu, XLi, LNing, HRong, YShang, YWang, YFu, XYChang, ZJ Biol Chem 280:20842-50

6.3.2.19

STUB1 (CHIP) ubiquitinates SMAD3

STUB1 (CHIP) ubiquitinates SMAD3 in the absence of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 2187365

Reactome DB_ID: 2187371

Ub-SMAD3 [cytosol]

Ub-SMAD3

Reactome DB_ID: 170855

EQUAL

425

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752187371Database 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=2187371ReactomeR-HSA-2187371

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-2187371.1

Reactome DB_ID: 975970

EQUAL

303

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2187365

Reactome Database ID Release 752187377Database 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=2187377Reactome Database ID Release 752187368Database 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=2187368ReactomeR-HSA-2187368

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-2187368.1

Degradation of ubiquitinated SMAD3

SMAD3, ubiquitinated by STUB1 (CHIP), is degraded in a proteasome-dependent manner. STUB1-mediated downregulation of SMAD3 level happens in the absence of TGF-beta stimulation. STUB1 may therefore keep the basal level of SMAD3 low in the absence of TGF-beta signaling (Li et al. 2004, Xin et al. 2005).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2187371

Reactome Database ID Release 752187382Database 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=2187382ReactomeR-HSA-2187382

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-2187382.1

PMEPA1 sequesters phosphorylated SMAD2/3

PMEPA1 binds phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers (Watanabe et al. 2010).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome DB_ID: 2187347

UniProt:Q969W9 PMEPA1

PMEPA1

STAG1TMEPAIPMEPA1FUNCTION Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA recruits the intracellular signal transducer and transcriptional modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by the receptor, SMAD2 and SMAD3 then form a heteromeric complex with SMAD4 that translocates to the nucleus to regulate transcription. Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal (PubMed:20129061, PubMed:24627487). Also involved in down-regulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR, probably by recruiting NEDD4 (PubMed:18703514).SUBUNIT Interacts with NEDD4 (via PPxY motifs). Interacts with AR. Interacts with LDLRAD4. Interacts (via the SMAD interaction motif) with SMAD2 and SMAD3.TISSUE SPECIFICITY Highest expression in prostate. Also expressed in ovary.INDUCTION Up-regulated by androgen and TGF-beta (at protein level).DOMAIN The PPxY motifs mediate interaction with NEDD4.DOMAIN The SMAD interaction motif is required for interaction with SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.SIMILARITY Belongs to the PMEPA1 family.

UniProtQ969W9

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287

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Reactome DB_ID: 2187343

p-2S-SMAD2/3:PMEPA1 [early endosome membrane]

p-2S-SMAD2/3:PMEPA1

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome DB_ID: 2187347

EQUAL

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Reactome Database ID Release 752187343Database 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=2187343ReactomeR-HSA-2187343

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-2187343.1Reactome Database ID Release 752187355Database 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=2187355ReactomeR-HSA-2187355

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-2187355.120129061Pubmed2010TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signalingWatanabe, YItoh, SGoto, TOhnishi, EInamitsu, MItoh, FSatoh, KWiercinska, EYang, WShi, LTanaka, ANakano, NMommaas, AMShibuya, Hten Dijke, PKato, MMol Cell 37:123-34

PMEPA1 sequesters unphosphorylated SMAD2/3

PMEPA1 binds unphosphorylated SMAD2 and SMAD3 and prevents their phosphorylation in response to TGF-beta stimulation (Watanabe et al. 2010).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2186792

EQUAL

287

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171172

Reactome DB_ID: 2187341

SMAD2/3:PMEPA1 [plasma membrane]

SMAD2/3:PMEPA1

Reactome DB_ID: 2186792

EQUAL

287

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171172

Reactome Database ID Release 752187341Database 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=2187341ReactomeR-HSA-2187341

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-2187341.1Reactome Database ID Release 752187358Database 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=2187358ReactomeR-HSA-2187358

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-2187358.1

MTMR4 binds phosphorylated SMAD2/3

A protein phosphatase MTMR4, residing in the early endosome membrane, binds phosphorylated SMAD2 and SMAD3 (Yu et al. 2010).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome DB_ID: 2187404

UniProt:Q9NYA4 MTMR4

MTMR4

KIAA0647MTMR4ZFYVE11FUNCTION Dephosphorylates proteins phosphorylated on Ser, Thr, and Tyr residues and low molecular weight phosphatase substrate para-nitrophenylphosphate. Phosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3).TISSUE SPECIFICITY Expressed in brain, heart, kidney, spleen, liver, colon, testis, muscle, placenta, thyroid gland, pancreas, ovary, prostate, skin, peripheral blood, and bone marrow.DEVELOPMENTAL STAGE Expressed in fetal brain and fetal liver.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.

UniProtQ9NYA4

EQUAL

1195

EQUAL

Reactome DB_ID: 2187399

p-2S-SMAD2/3:MTMR4 [early endosome membrane]

p-2S-SMAD2/3:MTMR4

Converted from EntitySet in Reactome

Reactome DB_ID: 171182

Reactome DB_ID: 2187404

EQUAL

1195

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Reactome Database ID Release 752187399Database 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=2187399ReactomeR-HSA-2187399

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-2187399.1Reactome Database ID Release 752187405Database 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=2187405ReactomeR-HSA-2187405

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-2187405.120061380Pubmed2010MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomesYu, JPan, LQin, XChen, HXu, YChen, YTang, HJ Biol Chem 285:8454-62

MTMR4 dephosphorylates SMAD2/3

MTMR4 protein phosphatase dephosphorylates SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers and inhibiting transmission of TGF-beta signal to the nucleus (Yu et al. 2010).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2187399

Reactome DB_ID: 29356

Reactome DB_ID: 2187404

EQUAL

1195

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 171172

Reactome DB_ID: 29372

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2187399

GO0004722

GO molecular function

Reactome Database ID Release 752187410Database 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=2187410Reactome Database ID Release 752187401Database 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=2187401ReactomeR-HSA-2187401

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-2187401.1

Reactome Database ID Release 752173788Database 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=2173788ReactomeR-HSA-2173788

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-2173788.1

CBL binds TGFBR2

The E3 ubiquitin ligase CBL binds the cytoplasmic tail of plasma membrane-bound TGFBR2 (TGF-beta receptor 2) but not TGFBR1 (TGF-beta receptor 1). The tyrosine kinase binding (TKB) domain of CBL is involved in this interaction (Zuo et al. 2013).

Authored: Orlic-Milacic, M, 2013-08-16Reviewed: Chen, Ye-Guang, 2013-08-28Edited: May, B, 2013-08-18

Reactome DB_ID: 170842

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567

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Reactome DB_ID: 112199

UniProt:P22681 CBL

CBL

RNF55CBL2CBLFUNCTION Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:17094949). Ubiquitinates SPRED2 (PubMed:17094949). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719).SUBUNIT (Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.DOMAIN The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.DOMAIN The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.PTM Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK.PTM Ubiquitinated, leading to its degradation via the proteasome (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).MISCELLANEOUS This protein has one functional calcium-binding site.

UniProtP22681

EQUAL

906

EQUAL

Reactome DB_ID: 4332229

TGFBR2:CBL [plasma membrane]

TGFBR2:CBL

Reactome DB_ID: 170842

EQUAL

567

EQUAL

Reactome DB_ID: 112199

EQUAL

906

EQUAL

Reactome Database ID Release 754332229Database 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=4332229ReactomeR-HSA-4332229

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-4332229.1Reactome Database ID Release 754332235Database 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=4332235ReactomeR-HSA-4332235

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-4332235.123290524Pubmed2013c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-? type II receptorZuo, WeiHuang, FeiChiang, Y JeffreyLi, MengDu, JunDing, YiZhang, TingLee, Hyuk WooJeong, Lak ShinChen, YulingDeng, HaitengFeng, Xin-HuaLuo, ShiwenGao, ChunjiChen, Ye-GuangMol. Cell 49:499-510

6.3.2.19

CBL neddylates TGFBR2

CBL neddylates TGFBR2 on lysine residues K556 and K567. The E3 ubiquitin ligase activity of CBL is necessary for this modification, and the kinase activity of TGFBR2 is also required. CBL-mediated neddylation prolongs the half-life of TGFBR2, thereby enhancing signaling by the TGF-beta receptor complex. CBLB, a CBL-related protein, may cooperate with CBL in TGFBR2 neddylation (Zuo et al. 2013).

Authored: Orlic-Milacic, M, 2013-08-16Reviewed: Chen, Ye-Guang, 2013-08-28Edited: May, B, 2013-08-18

Reactome DB_ID: 4419896

NEDD8-AcM-UBE2M [cytosol]

NEDD8-AcM-UBE2M

NEDD8:UBC12

Reactome DB_ID: 4419894

UniProt:P61081 UBE2M

UBE2M

UBC12UBE2MFUNCTION Accepts the ubiquitin-like protein NEDD8 from the UBA3-NAE1 E1 complex and catalyzes its covalent attachment to other proteins. The specific interaction with the E3 ubiquitin ligase RBX1, but not RBX2, suggests that the RBX1-UBE2M complex neddylates specific target proteins, such as CUL1, CUL2, CUL3 and CUL4. Involved in cell proliferation.PATHWAY Protein modification; protein neddylation.SUBUNIT Interacts with UBA3 and RBX1. Interacts (acetylated at N-terminal methionine) with DCUN1D1 (via DCUN1 domain) (PubMed:28581483).DOMAIN Both the N-terminal docking peptide and the catalytic core domain must bind the UBA3-NAE1 complex simultaneously for optimal transfer of NEDD8.PTM The acetylation of Met-1 increases affinity for DCUN1D1 by about 2 orders of magnitude and is crucial for NEDD8 transfer to cullins.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UBC12 subfamily.

UniProtP61081

Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 111 and 76

111

EQUAL

S-(glycyl)-L-cysteine (Cys-Gly)ChEBI24411

modification

N-acetyl-L-methionine at 1

EQUAL

N-acetyl-L-methionine [MOD:00058]

EQUAL

183

EQUAL

Reactome DB_ID: 4419895

UniProt:Q15843 NEDD8

NEDD8

NEDD8FUNCTION Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity, and thus promotes polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins.SUBUNIT Directly interacts with NUB1 and AHR. Covalently attached to cullins and p53.TISSUE SPECIFICITY Highly expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, ovary, colon and leukocytes.PTM Cleavage of precursor form by UCHL3 or SENP8 is necessary for function.SIMILARITY Belongs to the ubiquitin family.

UniProtQ15843

Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 76 and 111

EQUAL

ChEBI23511

modification

EQUAL

Reactome Database ID Release 754419896Database 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=4419896ReactomeR-HSA-4419896

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-4419896.2

Reactome DB_ID: 4332229

Reactome DB_ID: 4419904

Neddylated TGFBR2 [plasma membrane]

Neddylated TGFBR2

Reactome DB_ID: 4332222

Inter-chain Crosslink via neddylated lysine at 556 and 76

556

EQUAL

neddylated lysine

Inter-chain Crosslink via neddylated lysine at 567 and 76

567

EQUAL

567

EQUAL

Reactome DB_ID: 4419907

Inter-chain Crosslink via neddylated lysine at 76 and 556

EQUAL

ChEBI30777

modification

EQUAL

Reactome DB_ID: 4419906

Inter-chain Crosslink via neddylated lysine at 567 and 76

567

EQUAL

Reactome Database ID Release 754419904Database 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=4419904ReactomeR-HSA-4419904

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-4419904.1

Reactome DB_ID: 112199

EQUAL

906

EQUAL

Reactome DB_ID: 8951627

N-acetyl-L-methionine at 1

EQUAL

183

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 4332229

Reactome Database ID Release 754332230Database 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=4332230Reactome Database ID Release 754332236Database 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=4332236ReactomeR-HSA-4332236

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-4332236.3

Reactome Database ID Release 752173789Database 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=2173789ReactomeR-HSA-2173789

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-2173789.121423151Pubmed2011TGF-? signalling is mediated by two autonomously functioning T?RI:T?RII pairsHuang, TaoDavid, LaurentMendoza, ValentínYang, YongVillarreal, MariaDe, KeyaSun, LuZheFang, XiaohongLópez-Casillas, FernandoWrana, JLHinck, Andrew PEMBO J. 30:1263-7620207738Pubmed2010Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamilyRadaev, SergeiZou, ZhongchengHuang, TaoLafer, Eileen MHinck, Andrew PSun, Peter DJ. Biol. Chem. 285:14806-1418243111Pubmed2008Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor bindingGroppe, JayHinck, Cynthia SSamavarchi-Tehrani, PZubieta, ChloeSchuermann, Jonathan PTaylor, Alexander BSchwarz, Patricia MWrana, JLHinck, Andrew PMol. Cell 29:157-68GO0007179

GO biological process

TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)

In normal cells and in the early stages of cancer development, signaling by TGF-beta plays a tumor suppressive role, as SMAD2/3:SMAD4-mediated transcription inhibits cell division by downregulating MYC oncogene transcription and stimulating transcription of CDKN2B tumor suppressor gene. In advanced cancers however, TGF-beta signaling promotes metastasis by stimulating epithelial to mesenchymal transition (EMT). TGFBR1 is recruited to tight junctions by binding PARD6A, a component of tight junctions. After TGF-beta stimulation, activated TGFBR2 binds TGFBR1 at tight junctions, and phosphorylates both TGFBR1 and PARD6A. Phosphorylated PARD6A recruits SMURF1 to tight junctions. SMURF1 is able to ubiquitinate RHOA, a component of tight junctions needed for tight junction maintenance, leading to disassembly of tight junctions, an important step in EMT (Wang et al. 2003, Ozdamar et al. 2005).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2012-04-10

TGFBR1 is recruited to tight junctions by PARD6A

TGFBR1 binds to PARD6A, a component of tight junctions, and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for interactions with PRKCZ, is necessary for binding to TGFBR1 (Ozdamar et al. 2005). PARD6A, bound to PARD3 and PRKCZ, is associated with tight junctions through JAM-A (Ebnet et al. 2001), which is bound to CGN (cingulin) (Bazzoni et al. 2000). CGN binds ARHGEF18 (p114RhoGEF), and ARHGEF18 recruits RHOA to tight junctions. Other components of the tight junction structure are not shown in this context (Terry et al. 2011). Junctional RHOA activity is required for maintenance of junctional integrity through regulation of actinomyosin cytoskeleton organization (Terry et al. 2011). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 were studied in the context of endogenous mouse tight junctions.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2134514

cell junctionGO0030054Tight Junction Complex:PARD6A:RHOA [cell junction]

Tight Junction Complex:PARD6A:RHOA

Reactome DB_ID: 2133770

PARD3:PARD6A:PRKCZ [cell junction]

PARD3:PARD6A:PRKCZ

Reactome DB_ID: 2134483

UniProt:Q05513 PRKCZ

PRKCZ

PRKCZPKC2FUNCTION Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis. Phosphorylates VAMP2 in vitro (PubMed:17313651).ACTIVITY REGULATION Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-410 (activation loop of the kinase domain) and Thr-560 (turn motif), need to be phosphorylated for its full activation. Phosphatidylinositol 3,4,5-trisphosphate might be a physiological activator (By similarity). Isoform 2: Constitutively active (By similarity).SUBUNIT Forms a ternary complex with SQSTM1 and KCNAB2. Forms another ternary complex with SQSTM1 and GABRR3. Forms a complex with SQSTM1 and MAP2K5 (By similarity). Interacts with PARD6A, PARD6B, PARD6G and SQSTM1. Part of a complex with PARD3, PARD6A or PARD6B or PARD6G and CDC42 or RAC1. Interacts with ADAP1/CENTA1. Forms a ternary complex composed of SQSTM1 and PAWR. Interacts directly with SQSTM1 (Probable). Interacts with IKBKB. Interacts (via the protein kinase domain) with WWC1. Forms a tripartite complex with WWC1 and DDR1, but predominantly in the absence of collagen. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with PDPK1 (via N-terminal region). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Interacts with VAMP2 (PubMed:17313651). Forms a complex with WDFY2 and VAMP2 (PubMed:17313651). Interacts with APPL1 (PubMed:26583432).TISSUE SPECIFICITY Expressed in brain, and to a lesser extent in lung, kidney and testis.DOMAIN The PB1 domain mediate mutually exclusive interactions with SQSTM1 and PARD6B.DOMAIN The C1 domain does not bind the diacylglycerol (DAG).PTM CDH5 is required for its phosphorylation at Thr-410. Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2. Phosphorylation at Thr-410 by PI3K activates the kinase.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily.

UniProtQ05513

EQUAL

592

EQUAL

Reactome DB_ID: 2134481

UniProt:Q8TEW0 PARD3

PARD3

PARD3PAR3PAR3AFUNCTION Adapter protein involved in asymmetrical cell division and cell polarization processes (PubMed:27925688, PubMed:10954424). Seems to play a central role in the formation of epithelial tight junctions (PubMed:27925688). Targets the phosphatase PTEN to cell junctions (By similarity). Involved in Schwann cell peripheral myelination (By similarity). Association with PARD6B may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly (By similarity). The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins (PubMed:10934474). Required for establishment of neuronal polarity and normal axon formation in cultured hippocampal neurons (PubMed:19812038, PubMed:27925688).SUBUNIT Interacts (via PDZ 1 domain) with F11R/JAM1, PARD6A and PARD6B. Isoform 2, but not at least isoform 3 interacts with PRKCZ. Interacts with PRCKI and CDH5. Interacts (via PDZ 3 domain) with PTEN (via C-terminus) (By similarity). Part of a complex with PARD6A or PARD6B, PRKCI or PRKCZ and CDC42 or RAC1. Component of a complex whose core is composed of ARHGAP17, AMOT, MPP5/PALS1, PATJ and PARD3/PAR3. Interacts with LIMK2, AURKA and AURKB. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Directly interacts with TIAM1 and TIAM2. Interacts with ECT2, FBF1 and SIRT2. Interacts (via coiled-coil domain) with FRMD4A (By similarity). Found in a complex with PARD3, CYTH1 and FRMD4A (By similarity). Interacts with SAPCD2 (PubMed:26766442). Interacts with PRKCA (PubMed:27925688).TISSUE SPECIFICITY Widely expressed.DOMAIN Contains a conserved N-terminal oligomerization domain (NTD) that is involved in oligomerization and is essential for proper subapical membrane localization.DOMAIN The second PDZ domain mediates interaction with membranes containing phosphoinositol lipids.PTM Acetylated. Deacetylated by SIRT2, thereby inhibiting Schwann cell peripheral myelination.PTM Phosphorylation at Ser-827 by PRKCZ and PRKCI occurs at the most apical tip of epithelial cell-cell contacts during the initial phase of tight junction formation and may promote dissociation of the complex with PARD6. EGF-induced Tyr-1127 phosphorylation mediates dissociation from LIMK2 (By similarity). Phosphorylation by AURKA at Ser-962 is required for the normal establishment of neuronal polarity (PubMed:19812038).MISCELLANEOUS Antibodies against PARD3 are present in sera from patients with cutaneous T-cell lymphomas.SIMILARITY Belongs to the PAR3 family.

UniProtQ8TEW0

EQUAL

1356

EQUAL

Reactome DB_ID: 2134480

UniProt:Q9NPB6 PARD6A

PARD6A

PARD6APAR6AFUNCTION Adapter protein involved in asymmetrical cell division and cell polarization processes. Probably involved in the formation of epithelial tight junctions. Association with PARD3 may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins (PubMed:10873802). Regulates centrosome organization and function. Essential for the centrosomal recruitment of key proteins that control centrosomal microtubule organization (PubMed:20719959).SUBUNIT Interacts with MAP2K5 (By similarity). Interacts with PARD3. Interacts with GTP-bound forms of CDC42, ARHQ/TC10 and RAC1. Interacts with the N-terminal part of PRKCI and PRKCZ. Part of a complex with PARD3, CDC42 or RAC1 and PRKCI or PRKCZ. Part of a complex with LLGL1 and PRKCI (By similarity). Interacts with human T-cell leukemia virus type I TAX protein. Interacts with MPP5 and CRB3. Interacts with TGFBR1; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with ECT2 ('Thr-359' phosphorylated form) and PRKCI. Interacts with DCTN1 and PCM1 (PubMed:20719959).TISSUE SPECIFICITY Expressed in pancreas, skeletal muscle, brain and heart. Weakly expressed in kidney and placenta.DOMAIN The pseudo-CRIB domain together with the PDZ domain is required for the interaction with Rho small GTPases.DOMAIN The PB1 domain mediates interactions with MAP2K5.DOMAIN The PDZ domain mediates the interaction with CRB3.PTM Phosphorylated by the TGF-beta receptor.SIMILARITY Belongs to the PAR6 family.

UniProtQ9NPB6

EQUAL

346

EQUAL

Reactome Database ID Release 752133770Database 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=2133770ReactomeR-HSA-2133770

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-2133770.1

Reactome DB_ID: 2134478

UniProt:Q9P2M7 CGN

CGN

CGNKIAA1319FUNCTION Probably plays a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier.SUBUNIT Homodimer (By similarity). Interacts with TJP1/ZO-1.TISSUE SPECIFICITY Localized on the cytoplasmic face of tight junctions of polarized epithelia and some endothelia. Expressed in pancreas, kidney, liver and lung, but not in skeletal muscle, placenta, brain or heart.DOMAIN Deletion of the ZO-1 interaction motif (ZIM) decreases but does not abolish colocalization with ZO-1.SIMILARITY Belongs to the cingulin family.

UniProtQ9P2M7

EQUAL

1197

EQUAL

Reactome DB_ID: 2134486

UniProt:Q6ZSZ5 ARHGEF18

ARHGEF18

KIAA0521ARHGEF18FUNCTION Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases. Its activation induces formation of actin stress fibers. Also acts as a GEF for RAC1, inducing production of reactive oxygen species (ROS). Does not act as a GEF for CDC42. The G protein beta-gamma (Gbetagamma) subunits of heterotrimeric G proteins act as activators, explaining the integrated effects of LPA and other G-protein coupled receptor agonists on actin stress fiber formation, cell shape change and ROS production. Required for EPB41L4B-mediated regulation of the circumferential actomyosin belt in epithelial cells (PubMed:22006950).SUBUNIT Interacts with SEPT9; the interaction may inhibit GEF activity (PubMed:15558029). Interacts with Gbetagamma subunits GNB1 and GNG2 (PubMed:14512443). Interacts with EPB41L4B (PubMed:22006950). Interacts with PATJ (via C-terminus) (PubMed:22006950).TISSUE SPECIFICITY Expressed in all tissues tested with highest expression in kidney and pancreas. Weakly or not expressed in liver, skeletal muscle and testis. Isoform 1: Expressed in eosinophils (PubMed:29601110). Isoform 2: Expressed in eosinophils (PubMed:29601110). Isoform 3: Expressed in eosinophils (PubMed:29601110). Isoform 4: Not detected in eosinophils (PubMed:29601110).

UniProtQ6ZSZ5

EQUAL

1173

EQUAL

Reactome DB_ID: 5665993

RHOA:GTP [plasma membrane]

RHOA:GTP

Reactome DB_ID: 29438

GTP [ChEBI:15996]

GTP

Guanosine 5'-triphosphate

ChEBI15996

Reactome DB_ID: 194510

UniProt:P61586 RHOA

RHOA

ARH12ARHARHOARHO12FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibiton of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity).FUNCTION (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.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. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958).SUBUNIT Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991).SUBUNIT (Microbial infection) Interacts with yopT from Yersinia pestis.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.DOMAIN The basic-rich region is essential for yopT recognition and cleavage.PTM (Microbial infection) Substrate for botulinum ADP-ribosyltransferase.PTM (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage.PTM (Microbial infection) AMPylation at Tyr-34 and Thr-37 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 (Microbial infection) Glycosylated at Tyr-34 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 Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 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-37 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).PTM Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity).PTM Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.SIMILARITY Belongs to the small GTPase superfamily. Rho family.

UniProtP61586

EQUAL

190

EQUAL

Reactome Database ID Release 755665993Database 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=5665993ReactomeR-HSA-5665993

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-5665993.1

Reactome DB_ID: 2134498

UniProt:Q9Y624 F11R

F11R

JCAMJAM1F11RUNQ264/PRO301FUNCTION Seems to play a role in epithelial tight junction formation. Appears early in primordial forms of cell junctions and recruits PARD3 (PubMed:11489913). The association of the PARD6-PARD3 complex may prevent the interaction of PARD3 with JAM1, thereby preventing tight junction assembly (By similarity). Plays a role in regulating monocyte transmigration involved in integrity of epithelial barrier (By similarity). Ligand for integrin alpha-L/beta-2 involved in memory T-cell and neutrophil transmigration (PubMed:11812992). Involved in platelet activation (PubMed:10753840).FUNCTION (Microbial infection) Acts as a receptor for Mammalian reovirus sigma-1.FUNCTION (Microbial infection) Acts as a receptor for Human Rotavirus strain Wa.SUBUNIT Interacts with the ninth PDZ domain of MPDZ (PubMed:11489913). Interacts with the first PDZ domain of PARD3 (PubMed:11489913). The association between PARD3 and PARD6B probably disrupts this interaction (By similarity). Interacts with ITGAL (via I-domain) (PubMed:15528364).SUBUNIT (Microbial infection) Interacts with Mammalian reovirus sigma-1 capsid protein.SUBUNIT (Microbial infection) Interacts with Human Rotavirus strain Wa vp4 capsid protein.TISSUE SPECIFICITY Expressed in endothelium, epithelium and leukocytes (at protein level).DOMAIN The Ig-like V-type 2 domain is necessary and sufficient for interaction with integrin alpha-L/beta-2.PTM N-glycosylated.SIMILARITY Belongs to the immunoglobulin superfamily.

UniProtQ9Y624

EQUAL

299

EQUAL

Reactome Database ID Release 752134514Database 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=2134514ReactomeR-HSA-2134514

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-2134514.2

Reactome DB_ID: 2187279

Reactome DB_ID: 2134509

Tight Junction Complex:TGFBR1:PARD6A:RHOA [cell junction]

Tight Junction Complex:TGFBR1:PARD6A:RHOA

Reactome DB_ID: 2134514

Reactome DB_ID: 2187279

Reactome Database ID Release 752134509Database 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=2134509ReactomeR-HSA-2134509

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-2134509.1Reactome Database ID Release 752134506Database 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=2134506ReactomeR-HSA-2134506

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-2134506.115761148Pubmed2005Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticityOzdamar, BBose, RBarrios-Rodiles, MWang, HRZhang, YWrana, JLScience 307:1603-921258369Pubmed2011Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesisTerry, SJZihni, CElbediwy, AVitiello, ELeefa Chong San, IVBalda, MSMatter, KNat Cell Biol 13:159-6610877843Pubmed2000Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludinBazzoni, GMartinez-Estrada, OMOrsenigo, FCordenonsi, MCiti, SDejana, EJ Biol Chem 275:20520-612953056Pubmed2003The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarityEbnet, KlausAurrand-Lions, MKuhn, AKiefer, FButz, SZander, KMeyer zu Brickwedde, MKSuzuki, AImhof, BAVestweber, DJ Cell Sci 116:3879-9111447115Pubmed2001The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM)Ebnet, KlausSuzuki, AHorikoshi, YHirose, TMeyer zu Brickwedde, MKOhno, SVestweber, DEMBO J 20:3738-48

TGFBR2 is recruited to tight junctions after TGF-beta stimulation

After TGF-beta stimulation, TGFBR2 binds TGFBR1 anchored to tight junctions through association with PARD6A (Ozdamar et al. 2005). FKBP1A (FKBP12) prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were studied in the context of endogenous mouse tight junctions.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2134509

Reactome DB_ID: 170865

Reactome DB_ID: 2134522

Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA [cell junction]

Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA

Reactome DB_ID: 2134514

Reactome DB_ID: 170840

Reactome Database ID Release 752134522Database 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=2134522ReactomeR-HSA-2134522

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-2134522.1

Reactome DB_ID: 2026007

EQUAL

108

EQUAL

Reactome Database ID Release 752134519Database 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=2134519ReactomeR-HSA-2134519

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-2134519.1

TGFBR2 phosphorylates TGFBR1 and PARD6A

TGFBR2 recruited to tight junctions after TGF-beta stimulation phosphorylates PARD6A on serine residue S345, and it also phosphorylates TGFBR1 (Ozdamar et al. 2005). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were used.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2134522

Reactome DB_ID: 113592

Reactome DB_ID: 2134534

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA [cell junction]

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA

Reactome DB_ID: 170841

Reactome DB_ID: 2134529

Tight Junction Complex:p-PARD6A:RHOA [cell junction]

Tight Junction Complex:p-PARD6A:RHOA

Reactome DB_ID: 2134503

EQUAL

190

EQUAL

Reactome DB_ID: 2134478

EQUAL

1197

EQUAL

Reactome DB_ID: 2134486

EQUAL

1173

EQUAL

Reactome DB_ID: 2134498

EQUAL

299

EQUAL

Reactome DB_ID: 2134528

PARD3:p-PARD6A:PRKCZ [cell junction]

PARD3:p-PARD6A:PRKCZ

Reactome DB_ID: 2134483

EQUAL

592

EQUAL

Reactome DB_ID: 2134481

EQUAL

1356

EQUAL

Reactome DB_ID: 2134533

O-phospho-L-serine at 345

345

EQUAL

346

EQUAL

Reactome Database ID Release 752134528Database 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=2134528ReactomeR-HSA-2134528

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-2134528.1Reactome Database ID Release 752134529Database 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=2134529ReactomeR-HSA-2134529

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-2134529.1Reactome Database ID Release 752134534Database 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=2134534ReactomeR-HSA-2134534

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-2134534.1

Reactome DB_ID: 29370

Reactome Database ID Release 752134532Database 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=2134532ReactomeR-HSA-2134532

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-2134532.1

SMURF1 binds phosphorylated PARD6A

SMURF1 ubiquitin ligase is recruited to tight junctions by binding to phosphorylated PARD6A (Ozdamar et al. 2005).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2134534

Reactome DB_ID: 975972

EQUAL

757

EQUAL

Reactome DB_ID: 2160929

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1 [plasma membrane]

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1

Reactome DB_ID: 2134534

Reactome DB_ID: 975972

EQUAL

757

EQUAL

Reactome Database ID Release 752160929Database 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=2160929ReactomeR-HSA-2160929

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-2160929.1Reactome Database ID Release 752160932Database 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=2160932ReactomeR-HSA-2160932

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-2160932.1

SMURF1 ubiquitinates RHOA

SMURF1, recruited to tight junctions through association with phosphorylated PARD6A, ubiquitinates RHOA, leading to RHOA degradation and disassembly of tight junctions (Ozdamar et al. 2005). Disassembly of tight junctions is an important step in epithelial to mesenchymal transition. SMURF1, but not SMURF2, decreases RHOA level, and this effect is proteasome dependent (Wang et al. 2003).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2160929

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 2160934

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1 [cell junction]

Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1

Reactome DB_ID: 2160929

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752160934Database 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=2160934ReactomeR-HSA-2160934

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-2160934.1Reactome Database ID Release 752160935Database 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=2160935ReactomeR-HSA-2160935

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-2160935.114657501Pubmed2003Regulation of cell polarity and protrusion formation by targeting RhoA for degradationWang, HRZhang, YOzdamar, BOgunjimi, AAAlexandrova, EThomsen, GHWrana, JLScience 302:1775-9

Disassembly of tight junctions

Ubiquitination of RHOA by SMURF1 leads to disassembly of tight junctions, an important step in epithelial to mesenchymal transition.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2160934

Reactome Database ID Release 752160931Database 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=2160931ReactomeR-HSA-2160931

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-2160931.1

Reactome Database ID Release 752173791Database 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=2173791ReactomeR-HSA-2173791

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-2173791.1

Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer

In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2012-04-10

SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009). The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003). SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000). MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012). JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

The SMAD2/3:SMAD4 complex transfers to the nucleus

The phosphorylated R-SMAD:CO-SMAD complex rapidly translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003) where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for I-SMADs. Thus, TGF-beta/SMAD signaling induces the expression of the negative regulators of the pathway (negative feedback loop).

Reactome DB_ID: 171175

Reactome DB_ID: 173511

p-2S-SMAD2/3:SMAD4 [nucleoplasm]

p-2S-SMAD2/3:SMAD4

Phospho-R-SMAD:CO-SMAD complex

Reactome DB_ID: 177103

EQUAL

552

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 177105

p-2S-SMAD2/3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S423,S425-SMAD3 [nucleoplasm]p-S465,S467-SMAD2 [nucleoplasm]

Reactome Database ID Release 75173511Database 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=173511ReactomeR-HSA-173511

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-173511.1Reactome Database ID Release 75173488Database 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=173488ReactomeR-HSA-173488

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-173488.212592392Pubmed2003An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activityXiao, ZLatek, RLodish, HFOncogene 22:1057-6911294908Pubmed2001Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent mannerKurisaki, AKose, SYoneda, YHeldin, Carl-HenrikMoustakas, AMol Biol Cell 12:1079-9116260601Pubmed2005Kinetic analysis of Smad nucleocytoplasmic shuttling reveals a mechanism for transforming growth factor beta-dependent nuclear accumulation of SmadsSchmierer, BHill, CSMol Cell Biol 25:9845-5810934479Pubmed2000The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylationXu, LChen, YGMassague, JNat Cell Biol 2:559-6219114992Pubmed2009Nucleocytoplasmic shuttling of Smad proteinsHill, Caroline SCell Res. 19:36-4620694664Pubmed2010Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signalingDai, FangyanDuan, XueyanLiang, Yao-YunLin, XiaFeng, Xin-HuaMethods Mol. Biol. 647:125-37

2.7.11

Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9

CDK8 in complex with cyclin C (CDK8:CCNC) and CDK9 in complex with cyclin T (CDK9:CCNT) are able to phosphorylate the linker region of SMAD2 and SMAD3. In SMAD3, CDK8/CDK9 preferentially targets threonine residue T179, although serine residues S208 and S213 can also be phosphorylated. In SMAD2, CDK8/9 preferentially targets threonine residue T220 (corresponds to T190 in the short isoform of SMAD2, SMAD2-2). Phosphorylation of serine residues that correspond to serines S208 and S213 of SMAD3 has not been examined. Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8/CDK9 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes SMAD2 and SMAD3 for ubiquitination and subsequent degradation (Alarcon et al. 2009).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173511

Reactome DB_ID: 29358

Reactome DB_ID: 2176487

p-T,2S-SMAD2/3:SMAD4 [nucleoplasm]

p-T,2S-SMAD2/3:SMAD4

Converted from EntitySet in Reactome

Reactome DB_ID: 2176482

p-T,2S-SMAD2/3 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T220,S465,S467-SMAD2 [nucleoplasm]p-T179,S423,S425-SMAD3 [nucleoplasm]

Reactome DB_ID: 177103

EQUAL

552

EQUAL

Reactome Database ID Release 752176487Database 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=2176487ReactomeR-HSA-2176487

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-2176487.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 2176485

CDK8:CCNC/ CDK9:CCNT [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

GO0004674

GO molecular function

Reactome Database ID Release 752176488Database 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=2176488Reactome Database ID Release 752176475Database 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=2176475ReactomeR-HSA-2176475

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-2176475.119914168Pubmed2009Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathwaysAlarcon, CZaromytidou, AIXi, QGao, SYu, JFujisawa, SBarlas, AMiller, ANManova-Todorova, KMacias, MJSapkota, GPan, DMassague, JCell 139:757-69

ATP1B4 binds SNW1

In fish, amphibian and avian species, ATP1B4 (aka X,K-ATPase subunit beta-m) functions as a subunit of Na/K-ATPase, located in the plasma membrane. In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain-containing protein 1 (SNW1 aka Ski-interacting protein, SKIP), a transcriptional regulator. This ATP1B4:SNW1 complex is able to modulate TGF-beta-mediated transcription by increasing mRNA levels of SMAD7, an inhibitor of TGF-beta signalling (Pestov et al. 2007).

Authored: Jassal, Bijay, 2014-02-05Reviewed: D'Eustachio, Peter, 2015-02-11Edited: Jassal, Bijay, 2014-02-05

Reactome DB_ID: 351663

UniProt:Q13573 SNW1

SNW1

SNW1SKIPSKIIPFUNCTION Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Is required in the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. Is proposed to recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD.FUNCTION (Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter.FUNCTION (Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters.SUBUNIT Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs). Interacts SKI, SMAD2,SMAD3, RBPJ, RB1, PABPN1, MAGEA1, SIRT1, FOXN3, U2AF2, PPIL1, DAXX and ATP1B4. Interacts with VDR and RXRA; preferentially associates with VDR:RXRA heterodimers (PubMed:9632709, PubMed:12529369). Interacts with NCOR2 (PubMed:10644367). Interacts with MAML1 (PubMed:21245387). Interacts with NOTCH1 NICD; the interaction involves multimerized NOTCH1 NICD (PubMed:21245387). Forms a complex with NOTCH1 NICD and MAML1; the association is dissociated by RBPJ (PubMed:21245387). Associates with positive transcription elongation factor b (P-TEFb) (PubMed:15905409). Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN (PubMed:18794151).SUBUNIT (Microbial infection) Interacts with human papillomavirus type-16 (HPV16) E7 protein.SUBUNIT (Microbial infection) Interacts with EBV EBNA2; EBNA2 competes with NCOR2 for interaction with SNW1.SIMILARITY Belongs to the SNW family.

UniProtQ13573

EQUAL

536

EQUAL

Reactome DB_ID: 939761

nuclear envelopeGO0005635

UniProt:Q9UN42 ATP1B4

ATP1B4

ATP1B4FUNCTION May act as a transcriptional coregulator during muscle development through its interaction with SNW1. Has lost its ancestral function as a Na,K-ATPase beta-subunit.SUBUNIT Associates with a SMAD7-transcriptional complex. Interacts with SNW1 and TOR1AIP1 (By similarity). According to PubMed:17592128, does not associate with known Na,K-ATPase alpha-subunits.TISSUE SPECIFICITY Highly expressed in skeletal muscle and at a lower level in heart.SIMILARITY Belongs to the X(+)/potassium ATPases subunit beta family.

UniProtQ9UN42

EQUAL

357

EQUAL

Reactome DB_ID: 5252105

ATP1B4:SNW1 [nucleoplasm]

ATP1B4:SNW1

Reactome DB_ID: 351663

EQUAL

536

EQUAL

Reactome DB_ID: 939761

EQUAL

357

EQUAL

Reactome Database ID Release 755252105Database 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=5252105ReactomeR-HSA-5252105

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-5252105.1Reactome Database ID Release 755252001Database 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=5252001ReactomeR-HSA-5252001

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-5252001.117592128Pubmed2007Evolution of Na,K-ATPase beta m-subunit into a coregulator of transcription in placental mammalsPestov, Nikolay BAhmad, NisarKorneenko, Tatiana VZhao, HaoRadkov, RossenSchaer, DanièleRoy, SophieBibert, StéphanieGeering, KäthiModyanov, Nikolai NProc. Natl. Acad. Sci. U.S.A. 104:11215-20

WWTR1 binds SMAD2/3:SMAD4 heterotrimer

In the cytosol of human embryonic stem cells, WWTR1 (TAZ) binds heterotrimer composed of two R-SMADs (SMAD2 and/or SMAD3) and SMAD4. This interaction involves the C-terminus of WWTR1 (TAZ) and the MH1 domain of SMAD proteins.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 1629773

UniProt:Q9GZV5 WWTR1

WWTR1

WWTR1TAZFUNCTION Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.SUBUNIT Binds to SLC9A3R2 via the PDZ motif at the plasma membrane. Binds to YWHAZ in vivo and in vitro through the phosphoserine-binding motif RSHSSP (By similarity). Interacts (via coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4. Interacts with MED15, PAX8 and NKX2-1. Interacts with TEAD1, TEAD2, TEAD3 and TEAD4.TISSUE SPECIFICITY Highly expressed in kidney, heart, placenta and lung. Expressed in the thyroid tissue.DOMAIN The PDZ-binding motif is essential for stimulated gene transcription. It localizes the protein into both punctate nuclear foci and plasma membrane-associated complexes (By similarity).DOMAIN Binds to transcription factors via its WW domain.PTM Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2 results in creation of 14-3-3 binding sites, retention in the cytoplasm, and functional inactivation. Phosphorylation results in the inhibition of transcriptional coactivation through YWHAZ-mediated nuclear export.

UniProtQ9GZV5

EQUAL

400

EQUAL

Reactome DB_ID: 171175

Reactome DB_ID: 2031357

WWTR1:p-2S-SMAD2/3:SMAD4 [cytosol]

WWTR1:p-2S-SMAD2/3:SMAD4

Reactome DB_ID: 1629773

EQUAL

400

EQUAL

Reactome DB_ID: 171175

Reactome Database ID Release 752031357Database 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=2031357ReactomeR-HSA-2031357

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-2031357.1Reactome Database ID Release 752031355Database 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=2031355ReactomeR-HSA-2031355

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-2031355.118568018Pubmed2008TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewalVarelas, XSakuma, RSamavarchi-Tehrani, PPeerani, RRao, BMDembowy, JYaffe, MBZandstra, PWWrana, JLNat Cell Biol 10:837-48

WWTR1:SMAD translocates to the nucleus

TGF-beta-dependent nuclear accumulation of SMAD2/3 and SMAD4 is mediated by WWTR1 (TAZ). WWTR1 does not affect phosphorylation of SMAD2/3 or the formation of SMAD2/3:SMAD4 trimers.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2031357

Reactome DB_ID: 2106580

WWTR1:p-2S-SMAD2/3:SMAD4 [nucleoplasm]

WWTR1:p-2S-SMAD2/3:SMAD4

Reactome DB_ID: 1629775

EQUAL

400

EQUAL

Reactome DB_ID: 173511

Reactome Database ID Release 752106580Database 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=2106580ReactomeR-HSA-2106580

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-2106580.1Reactome Database ID Release 752106579Database 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=2106579ReactomeR-HSA-2106579

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-2106579.1

WWTR1:SMAD stimulates transcription of SMAD7

Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SMAD7 in human hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SMAD7 gene in response to TGF-beta stimulation (Varelas et al. 2008). In fish, amphibian and avian species, ATP1B4 (aka X,K ATPase subunit beta m) functions as a subunit of Na/K ATPase, located in the plasma membrane. In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain containing protein 1 (SNW1 aka Ski interacting protein, SKIP), a transcriptional regulator. This ATP1B4:SNW1 complex is able to modulate TGF beta mediated transcription by increasing mRNA levels of SMAD7, an inhibitor of TGF beta signalling (Pestov et al. 2007).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2106587

ENSEMBL:ENSG00000101665 SMAD7

SMAD7

MADH7MADH8SMAD7

ENSEMBLENSG00000101665

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome Database ID Release 752106591Database 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=2106591ReactomeR-HSA-2106591

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-2106591.3

ACTIVATION

Reactome Database ID Release 755255397Database 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=5255397ReactomeR-HSA-5255397

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-5255397.1

Reactome DB_ID: 5252105

ACTIVATION

Reactome Database ID Release 752106584Database 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=2106584ReactomeR-HSA-2106584

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-2106584.1

Reactome DB_ID: 2106580

WWTR1:SMAD stimulates transcription of SERPINE1 while TGIF:SMAD and SMAD7 inhibit it

Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) in hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SERPINE1 gene in response to TGF-beta stimulation (Varelas et al. 2008). Binding of TGIF1 or TGIF2 to SMAD2/3:SMAD4 heterotrimer negatively regulates transcription of SERPINE1 (Wotton et al. 1999, Melhuish et al. 2001). SMAD7 can also bind PAI-1 promoter (and probably other TGF-beta-responsive promoters) and inhibit PAI-1 expression, probably by competing with SMAD2/3:SMAD4 binding (Zhang et al. 2007).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Reviewed: Chen, Ye-Guang, 2012-11-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2106592

ENSEMBL:ENSG00000106366 SERPINE1PLANH1SERPINE1PAI1

ENSEMBLENSG00000106366

Reactome DB_ID: 61271

UniProt:P05121 SERPINE1

SERPINE1

PLANH1SERPINE1PAI1FUNCTION Serine protease inhibitor. Inhibits TMPRSS7 (PubMed:15853774). Is a primary inhibitor of tissue-type plasminogen activator (PLAT) and urokinase-type plasminogen activator (PLAU). As PLAT inhibitor, it is required for fibrinolysis down-regulation and is responsible for the controlled degradation of blood clots (PubMed:8481516, PubMed:9207454, PubMed:17912461). As PLAU inhibitor, it is involved in the regulation of cell adhesion and spreading (PubMed:9175705). Acts as a regulator of cell migration, independently of its role as protease inhibitor (PubMed:15001579, PubMed:9168821). It is required for stimulation of keratinocyte migration during cutaneous injury repair (PubMed:18386027). It is involved in cellular and replicative senescence (PubMed:16862142). Plays a role in alveolar type 2 cells senescence in the lung (By similarity). Is involved in the regulation of cementogenic differentiation of periodontal ligament stem cells, and regulates odontoblast differentiation and dentin formation during odontogenesis (PubMed:25808697, PubMed:27046084).SUBUNIT Forms a heterodimer with TMPRSS7 (PubMed:15853774). Interacts with VTN (PubMed:7522053). Binds LRP1B; binding is followed by internalization and degradation (PubMed:11384978). Interacts with PPP1CB (PubMed:28296156). In complex with PLAU/uPA, interacts with PLAUR/uPAR (PubMed:15053742). Interacts with SORL1 and LRP1, either alone or in complex with PLAU; these interactions are abolished in the presence of LRPAP1/RAP (PubMed:15053742). The ternary complex composed of PLAUR-PLAU-PAI1 also interacts with SORL1 (PubMed:15053742). Also interacts with SORL1, when complexed to PLAT/tPA (PubMed:15053742).TISSUE SPECIFICITY Expressed in endothelial cells (PubMed:2430793, PubMed:3097076). Found in plasma, platelets, and hepatoma and fibrosarcoma cells.PTM Inactivated by proteolytic attack of the urokinase-type (u-PA) and the tissue-type (TPA), cleaving the 369-Arg-|-Met-370 bond.SIMILARITY Belongs to the serpin family.

UniProtP05121

EQUAL

402

EQUAL

Reactome Database ID Release 752106586Database 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=2106586ReactomeR-HSA-2106586

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-2106586.311427533Pubmed2001TGIF2 interacts with histone deacetylase 1 and represses transcriptionMelhuish, TAGallo, CMWotton, DJ Biol Chem 276:32109-1417438144Pubmed2007Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formationZhang, SupingFei, TengZhang, LixiaZhang, RanChen, FengNing, YuanhengHan, YunaFeng, Xin-HuaMeng, AnmingChen, Ye-GuangMol. Cell. Biol. 27:4488-9910199400Pubmed1999A Smad transcriptional corepressorWotton, DLo, RSLee, SMassague, JCell 97:29-39

ACTIVATION

Reactome Database ID Release 752106588Database 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=2106588ReactomeR-HSA-2106588

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-2106588.1

Reactome DB_ID: 2106580

INHIBITION

Reactome Database ID Release 752186613Database 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=2186613ReactomeR-HSA-2186613

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-2186613.1

Reactome DB_ID: 2186606

p-2S-SMAD2/3:SMAD4:TGIF:HDAC1 [nucleoplasm]

p-2S-SMAD2/3:SMAD4:TGIF:HDAC1

Reactome DB_ID: 173511

Converted from EntitySet in Reactome

Reactome DB_ID: 2186609

TGIF [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTGIF2 [nucleoplasm]TGIF1 [nucleoplasm]

UniProtQ9GZN2UniProtQ15583

Reactome DB_ID: 205021

UniProt:Q13547 HDAC1

HDAC1

HDAC1RPD3L1FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation.SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex. Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Component of a RCOR/GFI/KDM1A/HDAC complex. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2. The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. Associates with the 9-1-1 complex; interacts with HUS1. Found in a complex with DNMT3A and HDAC7. Interacts with the non-histone region of MACROH2A1. Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation. Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity. Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity. In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter. Interacts with TSHZ3 (via N-terminus); the interaction is direct. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21. Interacts with CDKN1A/p21. Interacts with CDK5 complexed to CDK5R1 (p25). Interacts directly with GFI1 and GFI1B. Interacts with NR1D2 (via C-terminus). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity. Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, DNMT1, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541. Interacts with KDM5A (By similarity). Interacts with DNTTIP1 (PubMed:25653165). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Interacts with CCAR2 (PubMed:21030595). Interacts with PPHLN1 (PubMed:17963697). Found in a complex with YY1, SIN3A and GON4L (By similarity). Interacts with CHD4 (PubMed:27616479). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SIN3A (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with ZBTB7A (PubMed:25514493). Interacts with SMAD4; positively regulated by ZBTB7A (PubMed:25514493). Interacts with PACS2 (PubMed:29656858). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (PubMed:19433865). Interacts with ZNF638 (PubMed:30487602). Interacts with SPHK2 (PubMed:19729656). Interacts with ERCC6 (PubMed:26030138).TISSUE SPECIFICITY Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR, leading to its degradation by the proteasome. Ubiquitinated by KCTD11, leading to proteasomal degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily.

UniProtQ13547

EQUAL

482

EQUAL

Reactome Database ID Release 752186606Database 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=2186606ReactomeR-HSA-2186606

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-2186606.1

INHIBITION

Reactome Database ID Release 753009212Database 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=3009212ReactomeR-HSA-3009212

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-3009212.1

Reactome DB_ID: 178197

EQUAL

426

EQUAL

RNF111 binds SMAD7

E3 ubiquitin ligase RNF111 (Arkadia) binds SMAD7 in the nucleus (Koinuma et al. 2003).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 2186765

UniProt:Q6ZNA4 RNF111

RNF111

RNF111FUNCTION E3 ubiquitin-protein ligase (PubMed:26656854). Required for mesoderm patterning during embryonic development (By similarity). Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019, PubMed:16601693). Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7, inducing their proteasomal degradation and thereby enhancing the transcriptional activity of TGF-beta and BMP (PubMed:14657019, PubMed:16601693). In addition to enhance transcription of SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and subsequent degradation, coupling their activation with degradation, thereby ensuring that only effectors 'in use' are degraded (By similarity). Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL (PubMed:17591695). Associates with UBE2D2 as an E2 enzyme (PubMed:22411132). Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates (PubMed:23751493). Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (PubMed:23751493). Mediates ubiquitination and degradation of sumoylated PML (By similarity). The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs) (By similarity).ACTIVITY REGULATION Binds free ubiquitin non-covalently via its RING-type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin-protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer (PubMed:26656854). Interacts with SMAD6, SMAD7, AXIN1, AXIN2 and SKIL isoform SNON (PubMed:16601693, PubMed:17591695). Interacts with (phosphorylated) SMAD2 and SMAD3 (By similarity). Part of a complex containing RNF111, AXIN1 and SMAD7 (PubMed:16601693). Interacts (via SIM domains) with SUMO1 and SUMO2 (PubMed:23086935).TISSUE SPECIFICITY Broadly expressed.DOMAIN The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate.DOMAIN The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin (PubMed:26656854). Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and stimulates ubiquitin transfer (By similarity).SIMILARITY Belongs to the Arkadia family.

UniProtQ6ZNA4

EQUAL

994

EQUAL

Reactome DB_ID: 2186769

SMAD7:RNF111 [nucleoplasm]

SMAD7:RNF111

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Reactome DB_ID: 2186765

EQUAL

994

EQUAL

Reactome Database ID Release 752186769Database 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=2186769ReactomeR-HSA-2186769

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-2186769.1Reactome Database ID Release 752186771Database 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=2186771ReactomeR-HSA-2186771

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-2186771.114657019Pubmed2003Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7Koinuma, DShinozaki, MKomuro, AGoto, KSaitoh, MHanyu, AEbina, MNukiwa, TMiyazawa, KImamura, TMiyazono, KEMBO J 22:6458-70

6.3.2.19

RNF111 ubiquitinates SMAD7

RNF111 (Arkadia) polyubiquitinates SMAD7 (Koinuma et al. 2003). This was inferred from studies using recombinant mouse Smad7 and recombinant mouse Rnf111 expressed in human embryonic kidney cell line HEK293.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Ub [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBA52(1-76) [nucleoplasm]UBB(1-76) [nucleoplasm]UBC(533-608) [nucleoplasm]UBC(153-228) [nucleoplasm]UBC(609-684) [nucleoplasm]UBB(77-152) [nucleoplasm]UBC(1-76) [nucleoplasm]RPS27A(1-76) [nucleoplasm]UBB(153-228) [nucleoplasm]UBC(381-456) [nucleoplasm]UBC(229-304) [nucleoplasm]UBC(77-152) [nucleoplasm]UBC(457-532) [nucleoplasm]UBC(305-380) [nucleoplasm]

Reactome DB_ID: 2186769

Reactome DB_ID: 2186778

Ub-SMAD7 [nucleoplasm]

Ub-SMAD7

Reactome DB_ID: 178197

EQUAL

426

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome Database ID Release 752186778Database 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=2186778ReactomeR-HSA-2186778

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-2186778.1

Reactome DB_ID: 2186765

EQUAL

994

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2186769

Reactome Database ID Release 752186782Database 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=2186782Reactome Database ID Release 752186785Database 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=2186785ReactomeR-HSA-2186785

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-2186785.1

Degradation of Ub-SMAD7

After ubiquitination by RNF111 (Arkadia), ubiquitinated SMAD7 is degraded in a proteasome dependent way. Therefore, RNF111 has a positive effect on trancription initiated by TGF-beta signaling. However, TGF-beta signaling ultimately results in a decrease of RNF111 mRNA level, enabling negative-feedback regulation of TGF-beta signal by SMAD7. RNF111 may fine tune the duration of cellular response to TGF-beta signal. Initially, RNF111 may enable signal propagation by inhibiting negative regulators of TGF-beta signaling, SKI/SKIL and SMAD7. Subsequent negative regulation of RNF111 expression by TGF-beta may allow the signaling cascade to be turned off (Koinuma et al. 2003).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2186778

Reactome Database ID Release 752186780Database 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=2186780ReactomeR-HSA-2186780

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-2186780.1

SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2

In response to TGF-beta stimulation, a complex composed of SMAD2/3:SMAD4 heterotrimer and RBL1 (p107), E2F4/5 and DP1/2 can be detected in the nucleus. Formation of this complex was confirmed by both co-immunoprecipitation of the endogenous complex from the human keratinocyte cell line HaCat and by protein interaction studies using tagged recombinant proteins. It is possible that cells contain pre-assembled cytosolic complexes of SMAD2/3, RBL1 (p107) and E2F4/5, that translocate to the nucleus after TGF-beta stimulation, when phosphorylated SMAD2/3 recruit SMAD4. The MH2 domain of SMAD3 establishes independent contacts with the N-termini of E2F4 (or E2F5) and unphosphorylated RBL1 (p107). RBL2 (p130), RB1 and E2F1 do not interact with SMAD2/3 (Chen et al. 2002).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2127252

RBL1:E2F4/5:DP1/2 [nucleoplasm]

RBL1:E2F4/5:DP1/2

p107:E2F4/5:DP1/2

Converted from EntitySet in Reactome

Reactome DB_ID: 1362227

TFDP1,TFDP2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTFDP2 [nucleoplasm]TFDP1 [nucleoplasm]

UniProtQ14188UniProtQ14186

Reactome DB_ID: 389104

UniProt:P28749 RBL1

RBL1

RBL1FUNCTION Key regulator of entry into cell division (PubMed:17671431). Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation (By similarity). Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression (By similarity). Controls histone H4 'Lys-20' trimethylation (By similarity). Probably acts as a transcription repressor by recruiting chromatin-modifying enzymes to promoters (By similarity). Potent inhibitor of E2F-mediated trans-activation (PubMed:8319904). May act as a tumor suppressor (PubMed:8319904).SUBUNIT Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (PubMed:17671431, PubMed:16360038). The complex exists in quiescent cells where it represses cell cycle-dependent genes (PubMed:17671431). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (PubMed:17671431). Interacts with AATF (PubMed:12450794). Interacts with KDM5A (PubMed:7935440). Interacts with KMT5B and KMT5C (By similarity). Interacts with USP4 (By similarity). Interacts with RBBP9 (By similarity).SUBUNIT (Microbial infection) Interacts with SV40 and JC virus large T antigens. Large T antigen, but not E1A, binds only to the unphosphorylated form.PTM Cell-cycle arrest properties are inactivated by phosphorylation on Thr-332, Ser-640, Ser-964 and Ser-975 by CDK4.SIMILARITY Belongs to the retinoblastoma protein (RB) family.

UniProtP28749

EQUAL

1068

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 1226069

E2F4,E2F5 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityE2F5 [nucleoplasm]E2F4 [nucleoplasm]

UniProtQ15329UniProtQ16254Reactome Database ID Release 752127252Database 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=2127252ReactomeR-HSA-2127252

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-2127252.1

Reactome DB_ID: 173511

Reactome DB_ID: 2127250

p-SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2 [nucleoplasm]

p-SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2

Reactome DB_ID: 2127252

Reactome DB_ID: 173511

Reactome Database ID Release 752127250Database 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=2127250ReactomeR-HSA-2127250

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-2127250.1Reactome Database ID Release 752127257Database 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=2127257ReactomeR-HSA-2127257

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-2127257.112150994Pubmed2002E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repressionChen, CRKang, YSiegel, PMMassague, JCell 110:19-32

MYC trancscription is negatively regulated by SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2 complex

Complex formed by RBL1 (p107), E2F4/5, DP1/2 and a trimer of phosphorylated R-SMADs (SMAD2/3) and SMAD4 (Co-SMAD) cooperatively binds to TIE (TGF-beta inhibitory element) and E2F sites in the MYC promoter and promotes cell-cycle independent inhibition of MYC transcription in response to TGF-beta stimulation (Chen et al. 2002).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2127254

ENSEMBL:ENSG00000136997 MYCBHLHE39MYC

ENSEMBLENSG00000136997

Reactome DB_ID: 188379

UniProt:P01106 MYC

MYC

BHLHE39MYCFUNCTION Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis (PubMed:24940000). Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release (By similarity).SUBUNIT Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX (PubMed:9680483). Interacts with TAF1C and SPAG9. Interacts with PARP10. Interacts with KDM5A and KDM5B. Interacts (when phosphorylated at Thr-58 and Ser-62) with FBXW7(PubMed:25775507, PubMed:17558397). Interacts with PIM2. Interacts with RIOX1. The heterodimer MYC:MAX interacts with ABI1; the interaction may enhance MYC:MAX transcriptional activity. Interacts with TRIM6 (By similarity). Interacts with NPM1; the binary complex is recruited to the promoter of MYC target genes and enhances their transcription (PubMed:25956029). Interacts with CIP2A; leading to the stabilization of MYC (PubMed:17632056).PTM Phosphorylated by PRKDC. Phosphorylation at Ser-329 by PIM2 leads to the stabilization of MYC (By similarity). Phosphorylation at Ser-62 by CDK2 prevents Ras-induced senescence. Phosphorylated at Ser-62 by DYRK2; this primes the protein for subsequent phosphorylation by GSK3B at Thr-58. Phosphorylation at Thr-58 and Ser-62 by GSK3 is required for ubiquitination and degradation by the proteasome.PTM Ubiquitinated by the SCF(FBXW7) complex when phosphorylated at Thr-58 and Ser-62, leading to its degradation by the proteasome. In the nucleoplasm, ubiquitination is counteracted by USP28, which interacts with isoform 1 of FBXW7 (FBW7alpha), leading to its deubiquitination and preventing degradation. In the nucleolus, however, ubiquitination is not counteracted by USP28 but by USP36, due to the lack of interaction between isoform 3 of FBXW7 (FBW7gamma) and USP28, explaining the selective MYC degradation in the nucleolus (PubMed:25775507,PubMed:17558397). Also polyubiquitinated by the DCX(TRUSS) complex. Ubiquitinated by TRIM6 in a phosphorylation-independent manner (By similarity).DISEASE A chromosomal aberration involving MYC may be a cause of a form of B-cell chronic lymphocytic leukemia. Translocation t(8;12)(q24;q22) with BTG1.BIOTECHNOLOGY POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors. When combined, these factors are sufficient to reprogram differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes.

UniProtP01106

EQUAL

439

EQUAL

Reactome Database ID Release 751484099Database 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=1484099ReactomeR-HSA-1484099

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-1484099.3

INHIBITION

Reactome Database ID Release 751484103Database 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=1484103ReactomeR-HSA-1484103

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-1484103.1

Reactome DB_ID: 2127250

SMAD2/3:SMAD4 heterotrimer binds SP1

TGF-beta (TGFB1) stimulates formation of a complex of SP1 transcription factor and SMAD2/3:SMAD4 heterotrimer. SMAD2 and SMAD4 bind to SP1 directly, through their C- and N-terminus, respectively (Feng et al. 2000).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 1592223

UniProt:P08047 SP1

SP1

SP1TSFP1FUNCTION Transcription factor that can activate or repress transcription in response to physiological and pathological stimuli. Binds with high affinity to GC-rich motifs and regulates the expression of a large number of genes involved in a variety of processes such as cell growth, apoptosis, differentiation and immune responses. Highly regulated by post-translational modifications (phosphorylations, sumoylation, proteolytic cleavage, glycosylation and acetylation). Binds also the PDGFR-alpha G-box promoter. May have a role in modulating the cellular response to DNA damage. Implicated in chromatin remodeling. Plays an essential role in the regulation of FE65 gene expression. In complex with ATF7IP, maintains telomerase activity in cancer cells by inducing TERT and TERC gene expression. Isoform 3 is a stronger activator of transcription than isoform 1. Positively regulates the transcription of the core clock component ARNTL/BMAL1 (PubMed:10391891, PubMed:11371615, PubMed:11904305, PubMed:14593115, PubMed:16377629, PubMed:16478997, PubMed:16943418, PubMed:17049555, PubMed:18171990, PubMed:18199680, PubMed:18239466, PubMed:18513490, PubMed:18619531, PubMed:19193796, PubMed:20091743, PubMed:21798247, PubMed:21046154). Plays a role in the recruitment of SMARCA4/BRG1 on the c-FOS promoter. Plays a role in protecting cells against oxidative stress following brain injury by regulating the expression of RNF112 (By similarity).SUBUNIT Interacts with ATF7IP, ATF7IP2, BAHD1, POGZ, HCFC1, AATF and PHC2. Interacts with HLTF; the interaction may be required for basal transcriptional activity of HLTF. Interacts (deacetylated form) with EP300; the interaction enhances gene expression. Interacts with HDAC1 and JUN. Interacts with ELF1; the interaction is inhibited by glycosylation of SP1. Interaction with NFYA; the interaction is inhibited by glycosylation of SP1. Interacts with ATF7IP and TBP. Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a. Interacts with EGR1 (PubMed:10391891, PubMed:10976766, PubMed:12021324, PubMed:12847090, PubMed:12855699, PubMed:15691849, PubMed:16478997, PubMed:19106100, PubMed:19285002, PubMed:19302979, PubMed:19666599, PubMed:20121949, PubMed:21746878, PubMed:7592727, PubMed:9466902). Interacts with SMARCA4/BRG1. Interacts with RNF112 in an oxidative stress-regulated manner (By similarity). Interacts with ZBTB7A; ZBTB7A prevents the binding to GC-rich motifs in promoters and represses the transcriptional activity of SP1 (PubMed:12004059). Interacts with DDX3X; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription (PubMed:16818630).SUBUNIT (Microbial infection) Interacts with varicella-zoster virus IE62 protein.SUBUNIT (Microbial infection) Interacts with SV40 VP2/3 proteins. Interacts with SV40 major capsid protein VP1; this interaction leads to a cooperativity between the 2 proteins in DNA binding.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpr; the interaction is inhibited by SP1 O-glycosylation.TISSUE SPECIFICITY Up-regulated in adenocarcinomas of the stomach (at protein level). Isoform 3 is ubiquitously expressed at low levels.INDUCTION By insulin.DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on multiple serine and threonine residues. Phosphorylation is coupled to ubiquitination, sumoylation and proteolytic processing. Phosphorylation on Ser-59 enhances proteolytic cleavage. Phosphorylation on Ser-7 enhances ubiquitination and protein degradation. Hyperphosphorylation on Ser-101 in response to DNA damage has no effect on transcriptional activity. MAPK1/MAPK3-mediated phosphorylation on Thr-453 and Thr-739 enhances VEGF transcription but, represses FGF2-triggered PDGFR-alpha transcription. Also implicated in the repression of RECK by ERBB2. Hyperphosphorylated on Thr-278 and Thr-739 during mitosis by MAPK8 shielding SP1 from degradation by the ubiquitin-dependent pathway. Phosphorylated in the zinc-finger domain by calmodulin-activated PKCzeta. Phosphorylation on Ser-641 by PKCzeta is critical for TSA-activated LHR gene expression through release of its repressor, p107. Phosphorylation on Thr-668, Ser-670 and Thr-681 is stimulated by angiotensin II via the AT1 receptor inducing increased binding to the PDGF-D promoter. This phosphorylation is increased in injured artey wall. Ser-59 and Thr-681 can both be dephosphorylated by PP2A during cell-cycle interphase. Dephosphorylation on Ser-59 leads to increased chromatin association during interphase and increases the transcriptional activity. On insulin stimulation, sequentially glycosylated and phosphorylated on several C-terminal serine and threonine residues.PTM Acetylated. Acetylation/deacetylation events affect transcriptional activity. Deacetylation leads to an increase in the expression the 12(s)-lipooxygenase gene though recruitment of p300 to the promoter.PTM Ubiquitinated. Ubiquitination occurs on the C-terminal proteolytically-cleaved peptide and is triggered by phosphorylation.PTM Sumoylated with SUMO1. Sumoylation modulates proteolytic cleavage of the N-terminal repressor domain. Sumoylation levels are attenuated during tumorigenesis. Phosphorylation mediates SP1 desumoylation.PTM Proteolytic cleavage in the N-terminal repressor domain is prevented by sumoylation. The C-terminal cleaved product is susceptible to degradation.PTM O-glycosylated; Contains 8 N-acetylglucosamine side chains. Levels are controlled by insulin and the SP1 phosphorylation states. Insulin-mediated O-glycosylation locates SP1 to the nucleus, where it is sequentially deglycosylated and phosphorylated. O-glycosylation affects transcriptional activity through disrupting the interaction with a number of transcription factors including ELF1 and NFYA. Also inhibits interaction with the HIV1 promoter. Inhibited by peroxisomome proliferator receptor gamma (PPARgamma).MISCELLANEOUS In the hepatoma cell line Hep-G2, SP1 precursor mRNA may undergo homotype trans-splicing leading to the duplication of exons 2 and 3.SIMILARITY Belongs to the Sp1 C2H2-type zinc-finger protein family.

UniProtP08047

EQUAL

785

EQUAL

Reactome DB_ID: 173511

Reactome DB_ID: 2187302

p-2S-SMAD2/3:SMAD4:SP1 [nucleoplasm]

p-2S-SMAD2/3:SMAD4:SP1

Reactome DB_ID: 173511

Reactome DB_ID: 1592223

EQUAL

785

EQUAL

Reactome Database ID Release 752187302Database 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=2187302ReactomeR-HSA-2187302

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-2187302.1Reactome Database ID Release 752187309Database 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=2187309ReactomeR-HSA-2187309

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-2187309.111013220Pubmed2000Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-betaFeng, XHLin, XDerynck, REMBO J 19:5178-93

SMAD2/3:SMAD4:SP1 complex stimulates transcription of CDKN2B

SMAD2/3:SMAD4:SP1 complex binds SP1 and SMAD promoter elements of CDKN2B (p15-INK4B) gene and stimulates transcription of CDKN2B. CDKN2B inhibits the action of cyclin-dependent kinases CDK4 and CDK6 and may be an effector of TGF-beta induced cell cycle arrest (Feng et al. 2000).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2187305

ENSEMBL:ENSG00000147883 CDKN2B

CDKN2B gene

CDKN2BMTS2

ENSEMBLENSG00000147883

Reactome DB_ID: 182586

UniProt:P42772 CDKN2B

CDKN2B

CDKN2BMTS2FUNCTION Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest.SUBUNIT Heterodimer of CDKN2B with CDK4 or CDK6. Isoform 2 does not interact with CDK4 nor CDK6.TISSUE SPECIFICITY Isoform 2 is expressed in normal (keratinocytes, fibroblasts) and tumor cell lines.SIMILARITY Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.

UniProtP42772

EQUAL

138

EQUAL

Reactome Database ID Release 752187303Database 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=2187303ReactomeR-HSA-2187303

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-2187303.2

ACTIVATION

Reactome Database ID Release 752187304Database 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=2187304ReactomeR-HSA-2187304

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-2187304.1

Reactome DB_ID: 2187302

MEN1 binds SMAD2/3:SMAD4 heterotrimer

MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, binds SMAD2/3:SMAD4 heterotrimer through interaction with SMAD3. MEN1 likely acts as a trancriptional cofactor for SMAD2/3:SMAD4 and may be involved in transcriptional regulation of some SMAD2/3:SMAD4 target genes (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173511

Reactome DB_ID: 2186626

UniProt:O00255 MEN1

MEN1

SCG2MEN1FUNCTION Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair.SUBUNIT Component of the MLL-HCF complex, at least composed of KMT2A/MLL1, MEN1, ASH2L, RBBP5, DPY30, WDR5, HCFC1 and HCFC2. Component of the menin-associated histone methyltransferase complex, at least composed of KMT2B/MLL4, MEN1, ASH2L, RBBP5, DPY30 and WDR5. Interacts with POLR2B. Interacts with POLR2A phosphorylated at 'Ser-5', but not with the unphosphorylated, nor 'Ser-2' phosphorylated POLR2A forms. Interacts with FANCD2 and DBF4. Interacts with JUND (via MBM motif); inhibits the interaction of JUND with MAPK10 and the phosphorylation of JUND by MAP kinases MAPK8 and MAPK10 (PubMed:9989505, PubMed:22327296). Interacts with SMAD3, but not with SMAD2, nor SMAD4. Directly interacts with NFKB1, NFKB2 and RELA. Interacts with KMT2A (via MBM motif) (PubMed:25305204, PubMed:22936661, PubMed:22327296). The KMT2A-MEN1 complex interacts with PSIP1 with a greater affinity as MEN1 enhances interaction of KMT2A with PSIP1 (PubMed:25305204, PubMed:22327296). Interacts with the fusion protein KMT2A-MLLT3 (PubMed:25305204, PubMed:22936661).TISSUE SPECIFICITY Ubiquitous.DISEASE MEN1 inactivating mutations are responsible for hyperfunctioning of the parathyroid glands and subsequent primary hyperparathyroidism. Primary hyperparathyroidism can occur in isolation or in association with multiple endocrine neoplasia.

UniProtO00255

EQUAL

615

EQUAL

Reactome DB_ID: 2186642

p-2S-SMAD2/3:SMAD4:MEN1 [nucleoplasm]

p-2S-SMAD2/3:SMAD4:MEN1

Reactome DB_ID: 173511

Reactome DB_ID: 2186626

EQUAL

615

EQUAL

Reactome Database ID Release 752186642Database 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=2186642ReactomeR-HSA-2186642

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-2186642.1Reactome Database ID Release 752186643Database 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=2186643ReactomeR-HSA-2186643

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-2186643.111274402Pubmed2001Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signalingKaji, HCanaff, LLebrun, JJGoltzman, DHendy, GNProc Natl Acad Sci U S A 98:3837-4222275377Pubmed2012Impaired Transforming Growth Factor-? (TGF-?) Transcriptional Activity and Cell Proliferation Control of a Menin In-frame Deletion Mutant Associated with Multiple Endocrine Neoplasia Type 1 (MEN1)Canaff, LVanbellinghen, JFKaji, HGoltzman, DHendy, GNJ Biol Chem 287:8584-9715150273Pubmed2004Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2Sowa, HKaji, HHendy, GNCanaff, LKomori, TSugimoto, TChihara, KJ Biol Chem 279:40267-75

SMAD2/3:SMAD4 complex positively regulates JUNB transcription

SMAD2/3:SMAD4 heterotrimer binds SMAD binding site in the promoter of JUNB transcription factor and in cooperation with AP-1 transcription factors, which bind to an adjacent promoter element, stimulates transcription of JUNB gene (Wong et al. 1999).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2187294

ENSEMBL:ENSG00000171223 JUNB

JUNB gene

JUNB

ENSEMBLENSG00000171223

Reactome DB_ID: 2186795

UniProt:P17275 JUNB

JUNB

JUNBFUNCTION Transcription factor involved in regulating gene activity following the primary growth factor response. Binds to the DNA sequence 5'-TGA[CG]TCA-3'.SUBUNIT Binds DNA as a homodimer or as a heterodimer with another member of the Jun/Fos family. Interacts with ITCH (via its WW domains).INDUCTION By growth factors.PTM Ubiquitinated by ITCH, leading to its degradation.SIMILARITY Belongs to the bZIP family. Jun subfamily.

UniProtP17275

EQUAL

347

EQUAL

Reactome Database ID Release 752187293Database 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=2187293ReactomeR-HSA-2187293

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-2187293.310022869Pubmed1999Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor betaWong, CRougier-Chapman, EMFrederick, JPDatto, MBLiberati, NTLi, JMWang, XFMol Cell Biol 19:1821-30

ACTIVATION

Reactome Database ID Release 752187299Database 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=2187299ReactomeR-HSA-2187299

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-2187299.1

Reactome DB_ID: 173511

Reactome Database ID Release 752173796Database 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=2173796ReactomeR-HSA-2173796

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-2173796.1GO0045944

GO biological process

Downregulation of SMAD2/3:SMAD4 transcriptional activity

Transcriptional activity of SMAD2/3:SMAD4 heterotrimer can be inhibited by formation of a complex with SKI or SKIL (SNO), where SKI or SKIL recruit NCOR and possibly other transcriptional repressors to SMAD-binding promoter elements (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Higher levels of phosphorylated SMAD2 and SMAD3, however, may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001) through recruitment of SMURF2 (Bonni et al. 2001) or RNF111 i.e. Arkadia (Levy et al. 2007) ubiquitin ligases to SKI/SKIL by SMAD2/3. Therefore,the ratio of SMAD2/3 and SKI/SKIL determines the outcome: inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL. SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. SMAD4 can be monoubiquitinated by a nuclear ubiquitin ligase TRIM33 (Ecto, Ectodermin, Tif1-gamma). Monoubiquitination of SMAD4 disrupts SMAD2/3:SMAD4 heterotrimers and leads to SMAD4 translocation to the cytosol. In the cytosol, SMAD4 can be deubiquitinated by USP9X (FAM), reversing TRIM33-mediated negative regulation (Dupont et al. 2009). Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 primes SMAD2/3:SMAD4 complex for ubiquitination by NEDD4L and SMURF ubiquitin ligases. NEDD4L ubiquitinates SMAD2/3 and targets SMAD2/3:SMAD4 heterotrimer for degradation (Gao et al. 2009). SMURF2 monoubiquitinates SMAD2/3, leading to disruption of SMAD2/3:SMAD4 complexes (Tang et al. 2011). Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 complexes and inhibit SMAD-mediated transcription by recruitment of histone deacetylase HDAC1 to SMAD-binding promoter elements (Wotton et al. 1999, Melhuish et al. 2001). PARP1 can attach poly ADP-ribosyl chains to SMAD3 and SMAD4 within SMAD2/3:SMAD4 heterotrimers. PARylated SMAD2/3:SMAD4 complexes are unable to bind SMAD-binding DNA elements (SBEs) (Lonn et al. 2010). Phosphorylated SMAD2 and SMAD3 can be dephosphorylated by PPM1A protein phosphatase, leading to dissociation of SMAD2/3 complexes and translocation of unphosphorylated SMAD2/3 to the cytosol (Lin et al. 2006).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling

SKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex.

Reactome DB_ID: 173511

Converted from EntitySet in Reactome

Reactome DB_ID: 2186620

SKI/SKIL [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySKI [nucleoplasm]SKIL [nucleoplasm]

UniProtP12755UniProtP12757Converted from EntitySet in Reactome

Reactome DB_ID: 349716

NCOR1, NCOR2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNCOR1 [nucleoplasm]NCOR2 [nucleoplasm]

UniProtO75376UniProtQ9Y618

Reactome DB_ID: 177110

p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR [nucleoplasm]

p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR

Phospho-R-SMAD:CO-SMAD:SKI complex

Converted from EntitySet in Reactome

Reactome DB_ID: 2186620

Reactome DB_ID: 173511

Converted from EntitySet in Reactome

Reactome DB_ID: 349716

Reactome Database ID Release 75177110Database 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=177110ReactomeR-HSA-177110

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-177110.2Reactome Database ID Release 75173481Database 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=173481ReactomeR-HSA-173481

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-173481.110531062Pubmed1999Negative feedback regulation of TGF-beta signaling by the SnoN oncoproteinStroschein, SLWang, WeiZhou, SZhou, QLuo, KScience 286:771-410485843Pubmed1999The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signalingLuo, KStroschein, SLWang, WeiChen, DanMartens, EZhou, SZhou, QGenes Dev 13:2196-20610549282Pubmed1999Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signalingSun, YLiu, XEaton, ENLane, WSLodish, HFWeinberg, RAMol Cell 4:499-50911389444Pubmed2001TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradationBonni, SWang, HRCausing, CGKavsak, PStroschein, SLLuo, KWrana, JLNat Cell Biol 3:587-9510535941Pubmed1999SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signalingSun, YLiu, XNg-Eaton, ELodish, HFWeinberg, RAProc Natl Acad Sci U S A 96:12442-7

SMAD2/3 activation induces binding of RNF111/SMURF2 to SKI/SKIL

After phosphorylated SMAD2/3 accumulate in the nucleus in response to TGF-beta stimulation, E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007) and SMURF2 (Bonni et al. 2001) bind SKI/SKIL in complex with SMAD2/3:SMAD4 heterotrimer. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL (Levy et al. 2007). The role of SMURF2 was inferred from experiments involving human proteins only (Bonni et al. 2001).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 177110

Converted from EntitySet in Reactome

Reactome DB_ID: 2186743

RNF111/SMURF2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 2186744

p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR:RNF111/SMURF2 [nucleoplasm]

p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR:RNF111/SMURF2

Reactome DB_ID: 177110

Converted from EntitySet in Reactome

Reactome DB_ID: 2186743

Reactome Database ID Release 752186744Database 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=2186744ReactomeR-HSA-2186744

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-2186744.1Reactome Database ID Release 752186741Database 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=2186741ReactomeR-HSA-2186741

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-2186741.117591695Pubmed2007Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradationLevy, LHowell, MDas, DHarkin, SEpiskopou, VHill, CSMol Cell Biol 27:6068-83

6.3.2.19

Ubiquitination of SKI/SKIL by RNF111/SMURF2

E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007, Nagano et al. 2007) and SMURF2 (Bonni et al. 2001) ubiquitinate SKI/SKIL transcriptional repressors bound to activated SMAD2/3. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL. The role of SMURF2 was inferred from experiments involving human proteins only.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 2186744

Reactome DB_ID: 173511

Converted from EntitySet in Reactome

Reactome DB_ID: 349716

Reactome DB_ID: 2186733

Ub-SKI/Ub-SKIL [nucleoplasm]

Ub-SKI/Ub-SKIL

Converted from EntitySet in Reactome

Reactome DB_ID: 2186620

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome Database ID Release 752186733Database 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=2186733ReactomeR-HSA-2186733

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-2186733.1Converted from EntitySet in Reactome

Reactome DB_ID: 2186743

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2186744

Reactome Database ID Release 752186745Database 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=2186745Reactome Database ID Release 752186747Database 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=2186747ReactomeR-HSA-2186747

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-2186747.117510063Pubmed2007Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signalingNagano, YMavrakis, KJLee, KLFujii, TKoinuma, DSase, HYuki, KIsogaya, KSaitoh, MImamura, TEpiskopou, VMiyazono, KMiyazawa, KJ Biol Chem 282:20492-501

Degradation of ubiquitinated SKI/SKIL

SKI/SKIL ubiquitinated by RNF111 (Levy et al. 2007, Nagano et al. 2007) or SMURF2 (Bonni et al. 2001) are degraded in a proteasome dependent way, enabling transcription of SMAD2/3:SMAD4 target genes.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2186733

Reactome Database ID Release 752186767Database 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=2186767ReactomeR-HSA-2186767

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-2186767.1

TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus

E3 ubiquitin protein ligase TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) binds to the SMAD heterotrimer, composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3), in the nucleus (Dupont et al. 2009, Dupont et al. 2005, He et al. 2006).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173511

Reactome DB_ID: 870522

UniProt:Q9UPN9 TRIM33

TRIM33

RFG7KIAA1113TIF1GTRIM33FUNCTION Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homooligomer and heterooligomer with TRIM24 and TRIM28 family members. Interacts with SMAD4 in unstimulated cells. Found in a complex with SMAD2 and SMAD3 upon addition of TGF-beta. Interacts with SMAD2 and SMAD3. Interacts with SMAD4 under basal and induced conditions and, upon TGF-beta signaling, with activated SMAD2. Forms a ternary complex with SMAD4 and SMAD2 upon TGF-beta signaling.TISSUE SPECIFICITY Expressed in stem cells at the bottom of the crypts of the colon (at protein level). Expressed in colon adenomas and adenocarcinomas (at protein level). Expressed in brain, lung, liver, spleen, thymus, prostate, kidney, testis, heart, placenta, pancreas, small intestine, ovary, colon, skeletal muscle and hematopoietic progenitors.PTM Sumoylated with SUMO1.DISEASE A chromosomal aberration involving TRIM33 is found in papillary thyroid carcinomas (PTCs). Translocation t(1;10)(p13;q11) with RET. The translocation generates the TRIM33/RET (PTC7) oncogene.SIMILARITY Belongs to the TRIM/RBCC family.

UniProtQ9UPN9

EQUAL

1127

EQUAL

Reactome DB_ID: 870446

p-SMAD2/3:SMAD4:TRIM33 [nucleoplasm]

p-SMAD2/3:SMAD4:TRIM33

Reactome DB_ID: 173511

Reactome DB_ID: 870522

EQUAL

1127

EQUAL

Reactome Database ID Release 75870446Database 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=870446ReactomeR-HSA-870446

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-870446.1Reactome Database ID Release 75870538Database 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=870538ReactomeR-HSA-870538

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-870538.119135894Pubmed2009FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitinationDupont, SMamidi, ACordenonsi, MMontagner, MZacchigna, LAdorno, MMartello, GStinchfield, MJSoligo, SMorsut, LInui, MMoro, SModena, NArgenton, FNewfeld, SJPiccolo, SCell 136:123-3515820681Pubmed2005Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligaseDupont, SZacchigna, LCordenonsi, MSoligo, SAdorno, MRugge, MPiccolo, SCell 121:87-9916751102Pubmed2006Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathwayHe, WDorn, DCErdjument-Bromage, HTempst, PMoore, MAMassague, JCell 125:929-41

6.3.2.19

TRIM33 monoubiquitinates SMAD4

TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) monoubiquitinates nuclear SMAD4 on lysine residue K519. This leads to disruption of heterotrimeric complexes composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3). TRIM33 inhibits SMAD activity without affecting steady state levels of SMAD4 (Dupont et al. 2009, Dupont et al. 2005).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870446

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 870463

Ub-SMAD4 [nucleoplasm]

Ub-SMAD4

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 177103

EQUAL

552

EQUAL

Reactome Database ID Release 75870463Database 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=870463ReactomeR-HSA-870463

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-870463.1Converted from EntitySet in Reactome

Reactome DB_ID: 177105

Reactome DB_ID: 870522

EQUAL

1127

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 870446

Reactome Database ID Release 75870515Database 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=870515Reactome Database ID Release 75870449Database 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=870449ReactomeR-HSA-870449

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-870449.1

Ubiquitinated SMAD4 translocates from the nucleus to the cytosol

SMAD4 monoubiquitinated by TRIM33 translocates from the nucleus to the cytosol (Dupont et al. 2009, Dupont et al. 2005).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870463

Reactome DB_ID: 870482

Ub-SMAD4 [cytosol]

Ub-SMAD4

Reactome DB_ID: 170862

EQUAL

552

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 75870482Database 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=870482ReactomeR-HSA-870482

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-870482.1Reactome Database ID Release 75870477Database 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=870477ReactomeR-HSA-870477

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-870477.1

USP9X (FAM) binds to ubiquitinated SMAD4

In the cytosol, a ubiquitin hydrolase USP9X (FAM) binds to ubiquitinated SMAD4 (Dupont et al. 2009).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870482

Reactome DB_ID: 870499

UniProt:Q93008 USP9X

USP9X

USP9FAMUSP9XDFFRXFUNCTION Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-48'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration (PubMed:16322459, PubMed:18254724, PubMed:19135894, PubMed:24607389). Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein ARNTL/BMAL1 via its deubiquitinating activity (PubMed:29626158).SUBUNIT Interacts with SMAD4, MARK4, NUAK1 and BIRC5/survivin. Interacts with DCX. Interacts with OTUD4 and USP7; the interaction is direct (PubMed:25944111). Interacts with ARNTL/BMAL1 (PubMed:29626158).TISSUE SPECIFICITY Widely expressed in embryonic and adult tissues.MISCELLANEOUS Escapes X-inactivation.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ93008

EQUAL

2570

EQUAL

Reactome DB_ID: 870520

Ub-SMAD4:USP9X [cytosol]

Ub-SMAD4:USP9X

Reactome DB_ID: 170862

EQUAL

552

EQUAL

Reactome DB_ID: 870499

EQUAL

2570

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 75870520Database 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=870520ReactomeR-HSA-870520

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-870520.1Reactome Database ID Release 75870479Database 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=870479ReactomeR-HSA-870479

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-870479.3

USP9X (FAM) deubiquitinates SMAD4

USP9X (FAM) deubiquitinates SMAD4, thereby opposing the negative regulatory activity of TRIM33 (Ectodermin) (Dupont et al. 2009).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870520

Reactome DB_ID: 29356

Reactome DB_ID: 170862

EQUAL

552

EQUAL

Reactome DB_ID: 870499

EQUAL

2570

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 870520

Reactome Database ID Release 75870516Database 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=870516Reactome Database ID Release 75870437Database 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=870437ReactomeR-HSA-870437

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-870437.3

NEDD4L binds phosphorylated linker region of SMAD2/3

Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 creates a docking site for E3-ubiquitin ligase NEDD4L.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176420

EQUAL

975

EQUAL

Reactome DB_ID: 2176487

Reactome DB_ID: 2176495

p-T-2S-SMAD2/3:SMAD4:NEDDL4 [nucleoplasm]

p-T-2S-SMAD2/3:SMAD4:NEDDL4

Reactome DB_ID: 2176420

EQUAL

975

EQUAL

Reactome DB_ID: 2176487

Reactome Database ID Release 752176495Database 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=2176495ReactomeR-HSA-2176495

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-2176495.1Reactome Database ID Release 752176491Database 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=2176491ReactomeR-HSA-2176491

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-2176491.119917253Pubmed2009Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signalingGao, SAlarcon, CSapkota, GRahman, SChen, PYGoerner, NMacias, MJErdjument-Bromage, HTempst, PMassague, JMol Cell 36:457-68

NEDD4L ubiquitinates SMAD2/3

NEDD4L ubiquitinates nuclear SMAD2 and SMAD3 phosphorylated at the linker region by CDK8 or CDK9, targeting SMAD2 and SMAD3 for degradation.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176495

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 2176504

Ub-p-T-2S-SMAD2/3:SMAD4 [nucleoplasm]

Ub-p-T-2S-SMAD2/3:SMAD4

Reactome DB_ID: 2176487

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome Database ID Release 752176504Database 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=2176504ReactomeR-HSA-2176504

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-2176504.1

Reactome DB_ID: 2176420

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975

EQUAL

Reactome Database ID Release 752176502Database 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=2176502ReactomeR-HSA-2176502

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-2176502.1

Degradation of SMAD2/3:SMAD4 complex

NEDD4L-mediated ubiquitination of SMAD2/3 triggers degradation and ends transcriptional activity of SMAD2/3:SMAD4 complex.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2176504

Reactome Database ID Release 752176503Database 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=2176503ReactomeR-HSA-2176503

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-2176503.1

SMURF2 binds SMAD3 phosphorylated in the linker region

SMURF2 binds SMAD2/3:SMAD4 heterotrimer through ineraction with SMAD3. Phosphorylation of threonine T179 in the linker region of SMAD3 is critical for SMURF2 binding. SMURF2 also interacts with SMAD2 phosphorylated in the linker region.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 178202

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748

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Reactome DB_ID: 2176487

Reactome DB_ID: 2179277

p-T-2S-SMAD2/3:SMAD4:SMURF2 [nucleoplasm]

p-T-2S-SMAD2/3:SMAD4:SMURF2

Reactome DB_ID: 178202

EQUAL

748

EQUAL

Reactome DB_ID: 2176487

Reactome Database ID Release 752179277Database 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=2179277ReactomeR-HSA-2179277

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-2179277.1Reactome Database ID Release 752179274Database 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=2179274ReactomeR-HSA-2179274

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-2179274.1

6.3.2.19

SMURF2 monoubiquitinates SMAD3

SMURF2 monoubiquitinates SMAD3 on lysine residues in the MH2 domain. Lysines K333 and K378 are likely the major sites for monoubiquitination. Lysine K409 is also monoubiquitinated, and possibly lysine K341. Since lysines K333 and K378 are predicted to stabilize the interaction of SMAD3 with SMAD4, monoubiquitination of these lysine residues is expected to disrupt SMAD2/3:SMAD4 heterotrimer. SMURF2-mediated disruption of endogenous Smad2/3:Smad4 heterotrimers was demonstrated in mouse embryonic fibroblasts. SMURF2 also ubiquitinates SMAD2 phosphorylated in the linker region, but loss of Smurf2 has less impact on Smad2 ubiquitination than on Smad3 in vivo.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 2179277

Reactome DB_ID: 178202

EQUAL

748

EQUAL

Reactome DB_ID: 2179273

Ub-p-T-2S-SMAD2/3 [nucleoplasm]

Ub-p-T-2S-SMAD2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 2176482

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome Database ID Release 752179273Database 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=2179273ReactomeR-HSA-2179273

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-2179273.1

Reactome DB_ID: 177103

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552

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PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2179277

Reactome Database ID Release 752179275Database 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=2179275Reactome Database ID Release 752179276Database 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=2179276ReactomeR-HSA-2179276

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-2179276.1

TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer

Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 heterotrimer through interaction with SMAD2 and/or SMAD3. TGIF1 and TGIF2 recruit hystone deacetylase HDAC1 to SMAD2/3:SMAD4 heterotrimer.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173511

Converted from EntitySet in Reactome

Reactome DB_ID: 2186609

Reactome DB_ID: 205021

EQUAL

482

EQUAL

Reactome DB_ID: 2186606

Reactome Database ID Release 752186607Database 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=2186607ReactomeR-HSA-2186607

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-2186607.1

PARP1 binds SMAD2/3:SMAD4 heterotrimer

PARP1 (poly [ADP-ribose] polymerase 1) binds SMAD2/3:SMAD4 heterotrimers associated with DNA SMAD-binding elements (SBEs).

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 173511

Reactome DB_ID: 201568

UniProt:P09874 PARP1

PARP1

PARP1PPOLADPRTFUNCTION Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272, PubMed:25043379, PubMed:26344098). Mainly mediates glutamate and aspartate ADP-ribosylation of target proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of glutamate and aspartate residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:7852410, PubMed:9315851, PubMed:19764761, PubMed:25043379). Mediates the poly(ADP-ribosyl)ation of a number of proteins, including itself, APLF and CHFR (PubMed:17396150, PubMed:19764761). Also mediates serine ADP-ribosylation of target proteins following interaction with HPF1; HPF1 conferring serine specificity (PubMed:28190768). Probably also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (PubMed:30257210). Catalyzes the poly-ADP-ribosylation of histones in a HPF1-dependent manner (PubMed:27067600). Involved in the base excision repair (BER) pathway by catalyzing the poly-ADP-ribosylation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272). ADP-ribosylation follows DNA damage and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272). In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation (PubMed:26344098, PubMed:30356214). In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively (PubMed:27471034). Required for PARP9 and DTX3L recruitment to DNA damage sites (PubMed:23230272). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). Acts as a regulator of transcription: positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150 (PubMed:19344625). Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with TXK and EEF1A1 (PubMed:17177976). Involved in the synthesis of ATP in the nucleus, together with NMNAT1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257).SUBUNIT Homo- and heterodimer with PARP2. Interacts with APTX (PubMed:15044383). Component of a base excision repair (BER) complex, containing at least XRCC1, PARP1, PARP2, POLB and LRIG3 (By similarity). Interacts with SRY (PubMed:16904257). The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70 (By similarity). Interacts with TIAM2 (By similarity). Interacts with PARP3; leading to activate PARP1 in absence of DNA (PubMed:20064938). Interacts (when poly-ADP-ribosylated) with CHD1L (PubMed:19661379). Interacts with the DNA polymerase alpha catalytic subunit POLA1; this interaction functions as part of the control of replication fork progression (PubMed:9518481). Interacts with EEF1A1 and TXK (PubMed:17177976). Interacts with RNF4 (PubMed:19779455). Interacts with RNF146 (PubMed:21799911). Interacts with ZNF423 (PubMed:22863007). Interacts with APLF (PubMed:17396150). Interacts with SNAI1 (via zinc fingers); the interaction requires SNAI1 to be poly-ADP-ribosylated and non-phosphorylated (active) by GSK3B (PubMed:21577210). Interacts (when poly-ADP-ribosylated) with PARP9 (PubMed:23230272). Interacts with NR4A3; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (By similarity). Interacts (via catalytic domain) with PUM3; the interaction inhibits the poly-ADP-ribosylation activity of PARP1 and the degradation of PARP1 by CASP3 following genotoxic stress (PubMed:21266351). Interacts (via the PARP catalytic domain) with HPF1 (PubMed:27067600, PubMed:28190768). Interacts with ZNF365 (PubMed:23966166). Interacts with RRP1B (PubMed:19710015). Interacts with TIMELESS; the interaction is direct (PubMed:26344098). Interacts with CGAS; leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214).PTM Phosphorylated by PRKDC (PubMed:10467406). Phosphorylated by TXK (PubMed:17177976).PTM Poly-ADP-ribosylated on glutamate and aspartate residues by autocatalysis (PubMed:19764761). Poly-ADP-ribosylated by PARP2; poly-ADP-ribosylation mediates the recruitment of CHD1L to DNA damage sites (PubMed:19661379). ADP-ribosylated on serine by autocatalysis; serine ADP-ribosylation takes place following interaction with HPF1 (PubMed:28190768).PTM S-nitrosylated, leading to inhibit transcription regulation activity.

UniProtP09874

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1014

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Reactome DB_ID: 2187322

p-2S-SMAD2/3:SMAD4:PARP1 [nucleoplasm]

p-2S-SMAD2/3:SMAD4:PARP1

Reactome DB_ID: 173511

Reactome DB_ID: 201568

EQUAL

1014

EQUAL

Reactome Database ID Release 752187322Database 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=2187322ReactomeR-HSA-2187322

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-2187322.1Reactome Database ID Release 752187330Database 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=2187330ReactomeR-HSA-2187330

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-2187330.1