Maffè A, Comoglio P M
Institute for Cancer Research (IRCC), Univ. of Torino Medical School, Italy.
Eur J Morphol. 1998 Aug;36 Suppl:74-81.
The c-MET gene encodes the tyrosine kinase p190MET, the receptor for a molecule known as Scatter Factor (SF) or Hepatocyte Growth Factor (HGF). This molecule has biological activities on epithelial sheets, including mitogenesis, cell-cell dissociation, stimulation of migration into the extracellular matrix, induction of cell polarization and branched tubulogenesis. The p190MET receptor is a heterodimer of two (alphabeta) disulfide-linked protein subunits. The RON and SEA genes encode tyrosine kinases that are structurally homologous to the HGF receptor. The three members of MET family elicit the same array of unusual biological responses that include "scattering", growth, and induction of polarized tubular structures. Recently, we identified another family of genes (SEX genes) encoding putative receptors with structural similarities to the extracellular domain of the HGF receptor and large cytoplasmic domains with unknown functions. Receptor autophosphorylation triggers the signal transduction pathways inside the target cells. The phosphorylation of an intracellular site made of a specific two-tyrosine containing sequence, mediates interactions with multiple SH2-containing intracellular signaling molecules. The multifunctional docking site is conserved and functional in the receptors encoded by RON and SEA. Substitution of N1358, critical for recruiting the Grb2/SoS complex and activating the Ras pathway, results in the abrogation of the growth response, while mutation of H1351 into N, generating a docking site inefficient to activate the PI3-kinase pathway, stimulates growth but fails to support the induction of scattering and branched tubulogenesis. Activation of a third pathway, mediated by direct phosphorylation on tyrosine of STAT-3 plays a critical role in induction of cell polarization and formation of tubular structures.
c-MET基因编码酪氨酸激酶p190MET，它是一种名为散射因子（SF）或肝细胞生长因子（HGF）的分子的受体。该分子在上皮细胞层具有生物学活性，包括有丝分裂、细胞间解离、刺激向细胞外基质迁移、诱导细胞极化和分支小管形成。p190MET受体是由两个通过二硫键连接的蛋白质亚基（αβ）组成的异二聚体。RON和SEA基因编码与HGF受体在结构上同源的酪氨酸激酶。MET家族的三个成员引发相同一系列异常的生物学反应，包括“散射”、生长以及诱导极化管状结构的形成。最近，我们鉴定出了另一个基因家族（SEX基因），其编码的假定受体与HGF受体的细胞外结构域具有结构相似性，并且具有功能未知的大细胞质结构域。受体自身磷酸化触发靶细胞内的信号转导途径。由特定的含两个酪氨酸的序列组成的细胞内位点的磷酸化介导了与多种含SH2的细胞内信号分子的相互作用。多功能对接位点在RON和SEA编码的受体中是保守且有功能的。N1358的替代对于募集Grb2/SoS复合物和激活Ras途径至关重要，其替代会导致生长反应的消除，而将H1351突变为N，产生一个激活PI3激酶途径效率低下的对接位点，会刺激生长但无法支持散射和分支小管形成的诱导。由STAT-3酪氨酸直接磷酸化介导的第三条途径的激活在细胞极化诱导和管状结构形成中起关键作用。
