Covered on Genetics Home Reference: nonsyndromic hearing lossFrom NCBI Gene: Hepatocellular carcinomaRenal cell carcinoma, papillary, 1Osteofibrous dysplasiaDeafness, autosomal recessive 97From UniProt: 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. Renal cell carcinoma papillary (RCCP): A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. [MIM:605074] Defects in MET may be associated with gastric cancer. Hepatocellular carcinoma (HCC): A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. [MIM:114550] 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. Deafness, autosomal recessive, 97 (DFNB97): A form of non-syndromic sensorineural hearing loss with prelingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. [MIM:616705] Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.

     From NCBI Gene: This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016] From UniProt: 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. Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.

The following transcription factors affect gene expression:

• GR
• GR-alpha
• GR-beta
• p53
• Sp1
• NF-1
• Bach2
• p300

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).

Enzyme 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.

Molecular Function:

• Nucleotide Binding
• Double-Stranded Dna Binding
• Protein Tyrosine Kinase Activity
• Hepatocyte Growth Factor-Activated Receptor Activity
• Atp Binding
• Protein Phosphatase Binding
• Sequence-Specific Dna Binding
• Poly(A) Rna Binding

Biological Processes:

• Endothelial Cell Morphogenesis
• Transcription, Dna-Templated
• Regulation Of Transcription From Rna Polymerase Ii Promoter
• Apoptotic Process
• Signal Transduction
• Cell Surface Receptor Signaling Pathway
• Cell Proliferation
• Negative Regulation Of Autophagy
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Branching Morphogenesis Of An Epithelial Tube
• Positive Chemotaxis
• Semaphorin-Plexin Signaling Pathway
• Negative Regulation Of Hydrogen Peroxide-Mediated Programmed Cell Death
• Positive Regulation Of Endothelial Cell Chemotaxis
• Regulation Of Mrna Processing

Drug Bank:

• Crizotinib
• Cabozantinib