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. 2022 Jan 26;21:31. doi: 10.1186/s12943-022-01503-1

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — Different downstream signaling pathways activated through c-MET and its interactive other membrane receptors. HGF released through tumor associated fibroblast cells in microenvironment binds to c-MET and activates it through autophosphorylation of tyrosines Y1234 and Y1235 within the activation loop of the kinase domain and subsequent phosphorylation of tyrosines Y1349 and Y1356 near the -COOH terminus. Major adapter proteins and direct kinase substrates activated downstream in the c-MET pathway include growth factor receptor-bound protein 2 (GRB2), Grb2-associated adaptor protein 1 (GAB1), phosphatidylinositol 3-kinase (PI3K), son of sevenless (SOS), rat sarcoma oncogene homolog (RAS), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3/5 (STAT 3/5), SRC, SRC homology protein tyrosine phosphatase 2 (SHP2), SRC homology domain c-terminal adaptor homolog (SHC), phospholipase c-γ (PLC), Ras-related C3 botulinum toxin substrate 1 (RAC1), p21-activated kinase (PAK), focal adhesion kinase (FAK), AKT, and mammalian target of rapamycin (mTOR). Crosstalk between c-MET and various membrane protein partners, including the epidermal growth factor receptor (EGFR), the plexin B family, α6β4 integrin, and CD44, results in additional signaling response modulation