BioPAX pathway converted from "MET binds LRIG1" in the Reactome database. LEFT-TO-RIGHT MET binds LRIG1 LRIG1 can bind the MET receptor in the absence of HGF-mediated MET activation and trigger MET downregulation in a CBL-independent manner (Shattuck et al. 2007). MET targeting by the therapeutic antibody SAIT301 leads to LRIG1-mediated MET degradation through the lysosomal route. LRIG1-mediated MET downregulation requires ubiquitination of LRIG1 by an unknown ubiquitin ligase and can be inhibited by the ubiqitin hydrolase USP8, which deubiquitinates LRIG1 (Oh et al. 2014, Lee et al. 2014). Ubiquitinated LRIG1 binds to HGS (Hrs), a protein involved in clathrin-mediated endocytosis, and LRIG1 and MET co-localize with the lysosomal marker LAMP1 (Oh et al. 2014). Authored: Orlic-Milacic, Marija, 2016-06-14 Reviewed: Heynen, Guustaaf, 2016-07-11 Reviewed: Birchmeier, Walter, 2016-07-11 Edited: Orlic-Milacic, Marija, 2016-06-14 MET Hepatocyte growth factor receptor MET_HUMAN Reactome DB_ID: 419603 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P08581 MET MET FUNCTION Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity).FUNCTION (Microbial infection) Acts as a receptor for Listeria monocytogenes internalin InlB, mediating entry of the pathogen into cells.ACTIVITY REGULATION In its inactive state, the C-terminal tail interacts with the catalytic domain and inhibits the kinase activity. Upon ligand binding, the C-terminal tail is displaced and becomes phosphorylated, thus increasing the kinase activity.SUBUNIT Heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked. Binds PLXNB1. Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4 (By similarity). Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1356, interacts with INPPL1/SHIP2. Interacts with RANBP9 and RANBP10, as well as SPSB1, SPSB2, SPSB3 and SPSB4. SPSB1 binding occurs in the presence and in the absence of HGF, however HGF treatment has a positive effect on this interaction. Interacts with MUC20; prevents interaction with GRB2 and suppresses hepatocyte growth factor-induced cell proliferation. Interacts with GRB10. Interacts with PTPN1 and PTPN2. Interacts with LECT2; this interaction may have an antagonistic effect on receptor activation (PubMed:27334921). Interacts with HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity (PubMed:26517842).SUBUNIT (Microbial infection) Interacts via extracytoplasmic residues 25-656 with L.monocytogenes InlB; MET can bind HGF, its endogenous ligand, and InlB simultaneously (PubMed:11081636, PubMed:17662939). InlB probably dimerizes upon binding to MET, which encourages subsequent dimerization of MET (Probable).TISSUE SPECIFICITY Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. Expressed in metaphyseal bone (at protein level) (PubMed:26637977).DOMAIN The kinase domain is involved in SPSB1 binding.DOMAIN The beta-propeller Sema domain mediates binding to HGF.PTM Autophosphorylated in response to ligand binding on Tyr-1234 and Tyr-1235 in the kinase domain leading to further phosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. Dephosphorylated by PTPN1 and PTPN2.PTM Ubiquitinated. Ubiquitination by CBL regulates MET endocytosis, resulting in decreasing plasma membrane receptor abundance, and in endosomal degradation and/or recycling of internalized receptors.PTM (Microbial infection) Tyrosine phosphorylation is stimulated by L.monocytogenes InlB. Tyrosine phosphorylation is maximal 10-20 minutes after treatment with InlB and disappears by 60 minutes. The phosphorylated residues were not identified.DISEASE Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.DISEASE Defects in MET may be associated with gastric cancer.DISEASE A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes.DISEASE MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Homo sapiens NCBI Taxonomy 9606 UniProt P08581 25 EQUAL 1390 EQUAL Reactome Database ID Release 81 419603 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-419603 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome LRIG1 Leucine-rich repeats and immunoglobulin-like domains protein 1 precursor LIG1_HUMAN Reactome DB_ID: 197745 UniProt:Q96JA1 LRIG1 LRIG1 LIG1 FUNCTION Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.SUBUNIT Interacts (via extracellular LRR and Ig-like domains) with EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 (via extracellular domain) (PubMed:15282549). The physiological relevance of the interaction is controversial; LRIG1 may have low affinity for EGFR, and interaction may occur only when high levels of both proteins are present (PubMed:25765764).TISSUE SPECIFICITY Widely expressed.INDUCTION By EGF.DOMAIN Contains LRR and Ig-domains that can mediate low-affinity interaction with EGFR (PubMed:25765764). The LRRs and the Ig-domains are each sufficient for EGFR/ERBB1 binding. This interaction is abolished only when both the LRRs and the Ig-domains are deleted (PubMed:15282549). UniProt Q96JA1 35 EQUAL 1093 EQUAL Reactome Database ID Release 81 197745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-197745 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: MET:LRIG1 Reactome DB_ID: 8875375 1 1 Reactome Database ID Release 81 8875375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-8875375 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome Database ID Release 81 8875374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-8875374 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: 24828152 Pubmed 2014 USP8 modulates ubiquitination of LRIG1 for Met degradation Oh, Young Mi Lee, Saet Byoul Choi, Jaehyun Suh, Hye-Young Shim, Seonhui Song, Yun-Jeong Kim, Bogyou Lee, Ji Min Oh, Seung Ja Jeong, Yunju Cheong, Kwang Ho Song, Paul H Kim, Kyung-Ah Sci Rep 4:4980 17178829 Pubmed 2007 LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy Shattuck, David L Miller, Jamie K Laederich, Melanie Funes, Melanie Petersen, Heidi Carraway, Kermit L Sweeney, Colleen Mol. Cell. Biol. 27:1934-46 23208509 Pubmed 2014 Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody Lee, J M Kim, B Lee, S B Jeong, Y Oh, Y M Song, Y-J Jung, S Choi, J Lee, S Cheong, K H Kim, D U Park, H W Han, Y K Kim, G W Choi, H Song, P H Kim, K A Oncogene 33:34-43