BioPAX pathway converted from "SEMA4D interacts with Plexin-B1:ErbB2" in the Reactome database. LEFT-TO-RIGHT 2.7.10.2 SEMA4D interacts with Plexin-B1:ErbB2 Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. Upon binding of Sema4D to plexin-B1, the kinase activity of ErbB2 is increased resulting in tyrosine phosphorylation of both Plexin-B1 and ErbB2. ErbB2 has been shown to mediate Sema4D-induced growth cone collapse in hippocampal neurons by the activation of RhoA via plexinB1 and PDZRhoGEF/LARG.<br>Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038) but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. Authored: Garapati, P V, 2009-03-23 09:59:28 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-B1:ErbB2 Reactome DB_ID: 419629 plasma membrane GENE ONTOLOGY GO:0005886 PLXNB1 Plexin-B1 PLXB1_HUMAN Reactome DB_ID: 3008951 UniProt:O43157 PLXNB1 PLXNB1 KIAA0407 PLXN5 SEP FUNCTION Receptor for SEMA4D (PubMed:19843518, PubMed:20877282, PubMed:21912513). Plays a role in GABAergic synapse development (By similarity). Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12196628, PubMed:15210733). Plays a role in axon guidance, invasive growth and cell migration (PubMed:12198496).SUBUNIT Monomer, and heterodimer with PLXNB2 after proteolytic processing (PubMed:12533544, PubMed:17916560, PubMed:18411422, PubMed:18275816, PubMed:19843518, PubMed:20877282, PubMed:21912513). Binds RAC1 that has been activated by GTP binding (PubMed:11035813, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interaction with SEMA4D promotes binding of cytoplasmic ligands (PubMed:10520995, PubMed:12198496, PubMed:19843518). Interacts with PLXNA1 (By similarity). Interacts with ARHGEF11 and ARHGEF12 (PubMed:12196628). Interacts with ERBB2 (PubMed:15210733). Interacts with MET (PubMed:12198496, PubMed:15184888). Interacts with MST1R (PubMed:15184888). Interacts with RRAS (PubMed:19843518). Interacts with RHOD (PubMed:17916560). Interacts with RND1 (PubMed:12730235, PubMed:17916560, PubMed:18275816, PubMed:19843518). Interacts with NRP1 and NRP2 (PubMed:10520995).TISSUE SPECIFICITY Highly expressed in fetal kidney, and at slightly lower levels in fetal brain, lung and liver.PTM Phosphorylated on tyrosine residues by ERBB2 and MET upon SEMA4D binding.PTM Proteolytic processing favors heterodimerization with PLXNB2 and SEMA4D binding.SIMILARITY Belongs to the plexin family. Homo sapiens NCBI Taxonomy 9606 UniProt O43157 20 EQUAL 2135 EQUAL Reactome Database ID Release 83 3008951 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=3008951 Reactome R-HSA-3008951 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-HSA-3008951.1 Reactome http://www.reactome.org 1 ERBB2 ErbB2 Reactome DB_ID: 372889 UniProt:P04626 ERBB2 ERBB2 HER2 MLN19 NEU NGL FUNCTION Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization.FUNCTION In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.ACTIVITY REGULATION Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity.SUBUNIT Homodimer (PubMed:21454582). Heterodimer with EGFR, ERBB3 and ERBB4 (PubMed:10358079, PubMed:15093539, PubMed:21190959, PubMed:16978839). Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196 (PubMed:10805725). Interacts with PLXNB1 (PubMed:15210733). Interacts (when phosphorylated on Tyr-1248) with MEMO1 (PubMed:15156151). Interacts with MUC1; the interaction is enhanced by heregulin (HRG) (PubMed:12939402). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain) (PubMed:12975581). Interacts (when phosphorylated on Tyr-1248) with ERBIN (PubMed:12444095). Interacts with KPNB1, RANBP2, EEA1, CRM1 and CLTC (PubMed:16314522). Interacts with PTK6 (PubMed:18719096). Interacts with RPA194 and ACTB (PubMed:21555369). Interacts with PRKCABP, SRC and MYOC (By similarity). Interacts (preferentially with the tyrosine phosphorylated form) with CPNE3; this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner (PubMed:20010870). Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with SORL1; this interaction regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulates ERBB2-mediated signaling (PubMed:31138794). Interacts with SH3BGRL (PubMed:32381043).TISSUE SPECIFICITY Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.PTM Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit (Probable). Ligand-binding increases phosphorylation on tyrosine residues (PubMed:27134172, PubMed:33497358). Signaling via SEMA4C promotes phosphorylation at Tyr-1248 (PubMed:17554007). Dephosphorylated by PTPN12 (PubMed:27134172).POLYMORPHISM There are four alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012.DISEASE Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. UniProt P04626 23 EQUAL 1255 EQUAL Reactome Database ID Release 83 372889 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=372889 Reactome R-HSA-372889 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-HSA-372889.1 1 Reactome Database ID Release 83 419629 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=419629 Reactome R-HSA-419629 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-HSA-419629.1 SEMA4D dimer Reactome DB_ID: 373690 SEMA4D Semaphorin 4D Reactome DB_ID: 197744 UniProt:Q92854 SEMA4D SEMA4D C9orf164 CD100 SEMAJ FUNCTION Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling (PubMed:20877282). Regulates GABAergic synapse development (By similarity). Promotes the development of inhibitory synapses in a PLXNB1-dependent manner (By similarity). Modulates the complexity and arborization of developing neurites in hippocampal neurons by activating PLXNB1 and interaction with PLXNB1 mediates activation of RHOA (PubMed:19788569). Promotes the migration of cerebellar granule cells (PubMed:16055703). Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro) (PubMed:8876214). Induces endothelial cell migration through the activation of PTK2B/PYK2, SRC, and the phosphatidylinositol 3-kinase-AKT pathway (PubMed:16055703).SUBUNIT Homodimer (PubMed:20877282). Interacts with PLXNB2 (By similarity). Interacts with PLXNB1 (PubMed:10520995).TISSUE SPECIFICITY Strongly expressed in skeletal muscle, peripheral blood lymphocytes, spleen, and thymus and also expressed at lower levels in testes, brain, kidney, small intestine, prostate, heart, placenta, lung and pancreas, but not in colon and liver.SIMILARITY Belongs to the semaphorin family. UniProt Q92854 22 EQUAL 862 EQUAL Reactome Database ID Release 83 197744 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=197744 Reactome R-HSA-197744 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-HSA-197744.1 2 Reactome Database ID Release 83 373690 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=373690 Reactome R-HSA-373690 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-HSA-373690.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 113592 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=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 additional information MI MI:0361 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 29370 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=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 SEMA4D:ERBB2:p-Y-PLXNB1 SEMA4D:pPlexin-B1:ErbB2 complex Reactome DB_ID: 373695 ERBB2:p-Y-PLXNB1 pPlexin-B1:ErbB2 Reactome DB_ID: 419627 p-Y-PLXNB1 phosphorylated Plexin B1 Reactome DB_ID: 419609 O4'-phospho-L-tyrosine MOD MOD:00048 20 EQUAL 2135 EQUAL Reactome Database ID Release 83 419609 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=419609 Reactome R-HSA-419609 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-HSA-419609.1 1 1 Reactome Database ID Release 83 419627 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=419627 Reactome R-HSA-419627 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419627.2 1 1 Reactome Database ID Release 83 373695 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=373695 Reactome R-HSA-373695 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373695.2 ACTIVATION activeUnit: #Protein2 GENE ONTOLOGY GO:0004713 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 419656 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=419656 Reactome Database ID Release 83 373750 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=373750 Reactome R-HSA-373750 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-HSA-373750.1 18025083 Pubmed 2008 ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1 Swiercz, JM Worzfeld, T Offermanns, S J Biol Chem 283:1893-901 15210733 Pubmed 2004 Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2 Swiercz, JM Kuner, R Offermanns, S J Cell Biol 165:869-80