BioPAX pathway converted from "Role of ABL in ROBO-SLIT signaling" in the Reactome database. Role of ABL in ROBO-SLIT signaling Role of ABL in ROBO-SLIT signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Interaction of ABL with ROBO1:SLIT2 Interaction of ABL with ROBO1:SLIT2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9795257 1 plasma membrane GO 0005886 ROBO1:SLIT2 [plasma membrane] ROBO1:SLIT2 Reactome DB_ID: 9795252 1 UniProt:O89026 Robo1 Robo1 Robo1 Dutt1 FUNCTION Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuronal development (PubMed:10433822, PubMed:24560577). Interaction with the intracellular domain of FLRT3 mediates axon attraction towards cells expressing NTN1 (PubMed:24560577). In axon growth cones, the silencing of the attractive effect of NTN1 by SLIT2 may require the formation of a ROBO1-DCC complex (By similarity). Plays a role in the regulation of cell migration via its interaction with MYO9B; inhibits MYO9B-mediated stimulation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA (By similarity). May be required for lung development (PubMed:11734623).SUBUNIT Homodimer. Dimerization is mediated by the extracellular domain and is independent of SLIT liganding (By similarity). Interacts with SLIT1 (PubMed:10433822) Interacts with SLIT2 (By similarity). Interacts with FLRT3 (PubMed:24560577). Interacts with MYO9B (via Rho-GAP domain) (By similarity).TISSUE SPECIFICITY Detected in embryonic thalamus neurons (at protein level) (PubMed:24560577). Expressed in embryonal spinal chord. Expressed in embryonal lung, and in adult lung bronchial epithelial cells of large proximal airways.DEVELOPMENTAL STAGE Earliest and highest expression at 11 dpc. Expression is detected in developing somits, brain, neural tube, and pericardiac mesenchyme. By in situ hybridization is detected in marginal zones bordering the mitotically active periventricular region, weakly extending to the ventral aspect impinging on motor neuron columns. Also detected in the ventral third of the developing neural tube, and in spinal cord throughout the full length of the neural tube. Also detected at 17.5 dpc in lung mesenchyme. Expressed at 11.5 dpc in spinal cord, predominantly localized to postcrossing commissural axons.PTM Ubiquitinated. May be deubiquitinated by USP33.DISRUPTION PHENOTYPE Mice show defects in commissural axon guidance in spinal cord including midline recrossing and an altered lateral and ventral funiculi projection. The phenotype resembles that of a SLIT1;SLIT2;SLIT3 triple mutant. They also mimick a naturally occurring human homozygous deletion mutant detected in a small lung cancer cell line, frequently die at birth by respiratory failure with accompanying abnormal lung histology. Surviving mice develop bronchial hyperplasia.SIMILARITY Belongs to the immunoglobulin superfamily. ROBO family. Reactome http://www.reactome.org Mus musculus NCBI Taxonomy 10090 UniProt O89026 Chain Coordinates 26 EQUAL 1651 EQUAL Reactome DB_ID: 9795255 1 extracellular region GO 0005576 UniProt:Q9R1B9 Slit2 Slit2 Slit2 FUNCTION Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal cord development, may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal cord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system, appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration (By similarity).SUBUNIT Homodimer. Interacts with GREM1 (By similarity). Binds ROBO1 and ROBO2 with high affinity.TISSUE SPECIFICITY Expressed in developing eye, in the optic stalk, and in the ventral diencephalon.DEVELOPMENTAL STAGE According to PubMed:10864955 is expressed during retinal development by 14.5 dpc throughout the RGC layer, and is clearly restricted to the inner nuclear layer at 17.5 dpc. In the developing optic chiasm is strongly expressed at 12.5 dpc at the ventral midline of the diencephalon in the region in which the RGC axons enter the brain and turn to grow ventrally, the region expression includes the position of the glial knot. At 14.5 dpc expression is maintained at the ventral midline of the diencephalon, in a region directly dorsal to the site of axon divergence. Outside the developing brain. According to PubMed:10433822 prominently expressed in neural and mesodermally derived tissues. From 8.5 dpc to 9.5 dpc expressed strongly in the roof plate, floor plate, and notochord. Beginning at 10.5 dpc intense expression is also observed in the motor columns. By 13.5 dpc the expression decreased in the roof plate but is still retained in the floor plate and motor columns. In the rostral CNS between 8.5 dpc and 9.5 dpc expressed intensely in the dorsal neuroepithelium overlying the hindbrain, in the dorsal midline of the midbrain and forebrain, and in the ventral midbrain region. By 10.5 dpc to 11.5 dpc, additional intense expression is observed in the rhombic lip and the rostral midline. From 13.5 dpc to 17.5 dpc, the expression decreased dorsally and continued to be detected in the ventral mesencephalon and diencephalon. Outside neuronal development expressed between 8.5 dpc and 9.5 dpc in the clefts between the first, the second, and the third branchial arches. From 10.5 dpc to 11.5 dpc, expression is detected in the nasal pit, the developing eye, the otic vesicle, and the visceral grooves. From 13.5 dpc to 17.5 dpc expressed in the developing cochlea (in a pattern consistent with expression in the organ of Corti), in the olfactory epithelium and in the inner neuronal layer of the retina and in the optic nerve. At this stage also expressed in the tongue, in the tooth primordium, and in the outer root sheath of the whisker follicle in the layer surrounding the bulb. At 11.5 dpc is intensely expressed in the rostral lateral ridge flanking the forelimb buds and in lateral ridge tissue between the fore- and the hindlimb buds. Weak expression is observed in a segmented pattern in the posterior part of the sclerotome. Expression is notably absent in the base of the limb buds and weak expression is observed in the interdigital regions of the distal limb bud beginning at 11.5 dpc. By 13.5 dpc intensely expressed in interdigital mesenchyme.DOMAIN The leucine-rich repeat domain is sufficient for guiding both axon projection and neuronal migration, in vitro.DISRUPTION PHENOTYPE Mice show significant axon guidance errors in a variety of pathways, including corticofugal, callosal and thalamocortical tracts. Mice double-deficient in SLIT1 and SLIT2 show retinal axon guidance defects and a disorganized lateral olfactory tract (LOT). UniProt Q9R1B9 31 EQUAL 1529 EQUAL Reactome Database ID Release 81 9795257 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795257 Reactome R-MMU-390371 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-390371.1 Converted from EntitySet in Reactome Reactome DB_ID: 9799398 1 cytosol GO 0005829 ABL [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Abl2 [cytosol] Abl1 [cytosol] UniProt Q4JIM5 UniProt P00520 Reactome DB_ID: 9799400 1 SLIT2:ROBO1:ABL [plasma membrane] SLIT2:ROBO1:ABL Reactome DB_ID: 9795257 1 Converted from EntitySet in Reactome Reactome DB_ID: 9799398 1 Reactome Database ID Release 81 9799400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9799400 Reactome R-MMU-428873 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428873.1 Reactome Database ID Release 81 9799402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9799402 Reactome R-MMU-376141 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-376141.1 ABL (ABL1 or ABL2) binds directly, via its SH3 domain, to the CC3 motif in the cytoplasmic domain of human ROBO1 (Bashaw et al. 2000). 10892742 Pubmed 2000 Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor Bashaw, GJ Kidd, Thomas Murray, D Pawson, T Goodman, CS Cell 101:703-15 inferred by electronic annotation IEA GO IEA 2.7.10.2 Phosphorylation of ROBO1 by ABL kinase Phosphorylation of ROBO1 by ABL kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9799400 1 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 9805683 1 SLIT2:p-Y1073-ROBO1:ABL [plasma membrane] SLIT2:p-Y1073-ROBO1:ABL Reactome DB_ID: 9805681 1 p-Y1073-ROBO1:SLIT2 [plasma membrane] p-Y1073-ROBO1:SLIT2 Reactome DB_ID: 9805679 1 O4'-phospho-L-tyrosine at 1073 (in Homo sapiens) 1073 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 26 EQUAL 1651 EQUAL Reactome DB_ID: 9795255 1 31 EQUAL 1529 EQUAL Reactome Database ID Release 81 9805681 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9805681 Reactome R-MMU-428499 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428499.1 Converted from EntitySet in Reactome Reactome DB_ID: 9799398 1 Reactome Database ID Release 81 9805683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9805683 Reactome R-MMU-376027 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-376027.1 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9799400 GO 0004713 GO molecular function Reactome Database ID Release 81 9805684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9805684 Reactome Database ID Release 81 9805686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9805686 Reactome R-MMU-428888 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428888.1 ABL kinase (ABL1 or ABL2) phosphorylates the tyrosine residue Y1073 of the conserved CC1 motif (PTPYATT) in human ROBO1 (Bashaw et al. 2000). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 9884990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9884990 Reactome R-MMU-428890 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428890.1 ABL (ABL1 or ABL2) plays a dual role in the ROBO pathway. As a key enzymatic component in the signaling pathway, ABL supports repellent signaling (by recruiting the necessary actin binding proteins) and also feeds back on the receptor (by down regulating through phosphorylation) to adjust the sensitivity of the pathway.<br>ABL cooperates with multiple effectors, including the actin binding protein Capulet (Capt) and Orbit/MAST/CLASP, suggesting that ABL simultaneously coordinates the dynamics of two major cytoskeletal systems to achieve growth cone repellent guidance. 12441051 Pubmed 2002 A Drosophila homolog of cyclase-associated proteins collaborates with the Abl tyrosine kinase to control midline axon pathfinding Wills, Z Emerson, M Rusch, J Bikoff, J Baum, B Perrimon, N Van Vactor, D Neuron 36:611-22 15207230 Pubmed 2004 Hot +TIPS: guidance cues signal directly to microtubules Kalil, K Dent, EW Neuron 42:877-9 15207236 Pubmed 2004 The microtubule plus end tracking protein Orbit/MAST/CLASP acts downstream of the tyrosine kinase Abl in mediating axon guidance Lee, H Engel, U Rusch, J Scherrer, S Sheard, K Van Vactor, D Neuron 42:913-26 inferred by electronic annotation IEA GO IEA