MET in type 1 papillary renal cell carcinoma

MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of Tyr1234 and Tyr1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program; proliferation and survival (resistance to apoptotic signals), increased cell motility, cell dissociation (scattering), epithelial tubulogenesis, infiltration of tissues, and stimulation of angiogenesis (Appleman et al). The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of PI3K, or indirectly through the scaffolding protein GAB1. Phosphorylation of Tyr1349 and Tyr1356 of the multisubstrate docking site mediates interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2. GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signaling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways. (Description adapted from [https://en.wikipedia.org/wiki/C-Met Wikipedia]). MET is a proto-oncogene, meaning that regulated expression of the wild-type allele plays a role in normal physiologic processes, and malignant transformation occurs when MET activity is increased in- appropriately and/or constitutively activated (Appleman et al). Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.

MET 激活剂 HGF 通过诱导 MET 酶的催化活性，触发 Tyr1234 和 Tyr1235 的转磷酸化，这两个酪氨酸残基进而与多种信号转导分子相互作用，从而启动由 MET 驱动的生物活动系列，统称为侵袭性生长程序，包括增殖与存活（对凋亡信号的抵抗）、细胞运动能力增强、细胞分散（散射）、上皮管状形成、组织浸润以及血管生成刺激（Appleman 等人）。这些转导分子与 MET 的细胞内多底物对接位点直接或通过支架蛋白 GAB1 间接相互作用，如 GRB2、SHC、SRC 以及 PI3K 的 p85 调节亚基。多底物对接位点 Tyr1349 和 Tyr1356 的磷酸化介导与 GAB1、SRC 和 SHC 的相互作用，而仅 Tyr1356 参与GRB2、磷脂酶 C γ（PLC-γ）、p85 和 SHP2 的募集。GAB1 作为 MET 细胞反应的关键协调者，以高亲和力但低亲和性结合 MET 的细胞内区域。与 MET 相互作用后，GAB1 在多个酪氨酸残基上发生磷酸化，进而募集一系列信号效应分子，包括 PI3K、SHP2 和 PLC-γ。MET 对 GAB1 的磷酸化作用导致持续的信号传导，介导大部分下游信号通路。（描述改编自 [https://en.wikipedia.org/wiki/C-Met Wikipedia]）。MET 是一种原癌基因，意味着野生型等位基因的调控表达在正常生理过程中发挥作用，而 MET 活性不适当增加或持续激活时，将导致恶性转化（Appleman 等人）。磷酸化位点基于 PhosphoSitePlus（R）的信息添加，www.phosphosite.org。