Fig. 2

Mechanisms of MET and/or RON activation, signaling pathway, and biological consequence. Activation of MET and/or RON in CRAC cells, in general, is mediated through five events including ligand binding, activating mutation, receptor overexpression, aberrant splicing/alternative initiation, and transactivation through other RTKs such as EGFR and IGF-1R. HGF or MSP-induced MET and/or RON activation, a classical model, is functional through phosphorylation of several critical tyrosine residues and creates the C-terminal functional docking site, which recruits cytoplasmic molecules such as SOS and GRB2. The negative modulator c-CBL, a ubiquitin ligase, also binds the docking site and mediates MET and/or RON endocytosis and degradation. Multiple signaling pathways, such as RAS/MAP kinase, PI3K/AKT, Wnt/β-catenin, and TGF-β/SMAD pathways are activated upon MET and/or RON phosphorylation in CRAC cells, which creates a complex intracellular signaling network. The biological consequence is induction of EMT in CRAC cells leading to increased cellular survival, invasiveness, chemoresistance, and tumorigenic stemness. Briefly, activation of the RAS/MAP kinase cascade stimulates MET and/or RON-mediated activities such as cellular survival, invasiveness, chemoresistance, and tumorigenic stemness through regulating various gene expressions and cellular activities. Activated Erk1/2 also stimulates RSK-2, which regulates not only gene transcription but also cytoskeleton re-organization to cause the EMT-like phenotype. The PI3K-AKT pathway is essential in MET and/or RON-mediated cellular invasive growth and chemoresistance. Activated AKT inhibits GSK-3β by phosphorylation, resulting in MET and/or RON signaling cross-talking with the β-catenin pathway. AKT signaling is also linked to MET and/or RON-induced mTOR phosphorylation, which releases HIF-1α from the VHL. Similarly, mTOR stimulates p70S6 kinase, which activates certain transcription factors leading to increased gene expression. AKT also stimulates 14-3-3 phosphorylation, which displaces α6β4 integrin from its location at hemidesmosomes and re-localizes it to lamellipodia for cell motility. MET and/or RON activation also collaborates with TGF-β mediated Smad2/3 signaling and regulates CRAC cell EMT-like phenotypes, leading to cellular senescence, migration, and chemoresistance. Studies also show that MET and/or RON activation regulate β-catenin dephosphorylation by activating DVL, leading to β-catenin accumulation and nuclear translocation for activating gene transcription. ABL, Abelson murine leukemia viral oncogene homolog; AKT, BCL-2, B cell lymphoma-2; BIM, Bcl-2-like protein 11; CBL, protein kinase B; APC, adenomatous polyposis coli; AXIN, axis inhibition protein; CBP, CREB-binding protein; CREB, cAMP response element-binding protein; DVL, disheveled; Erk, extracellular signal-regulated kinase; FRAP, FKBP12-rapamycin-associated protein; FOXO3a, forkhead box O3; GRB2, growth factor receptor-bound protein; GSK, glycogen synthase kinase; MCL-1, myeloid cell leukemia 1; MEK, mitogen-activated protein kinase-kinase; MNK, mitogen-activated protein kinase interacting protein; mTOR, mammalian target of rapamycin; P70S6K, rribosomal protein S6 kinase beta-1; PDK1, 3-phosphoinositide-dependent protein kinase-1; PI3K, phosphatidyl-inositol 3 kinase; Raf, rapidly accelerated fibrosarcoma; RAS, reticular activating system; RSK-2, p90 ribosomal S6 kinase-2; Smad, small mothers against decapentaplegic; SOS, son of sevenless; TGF, transforming growth factor; VHL, von Hippel-Lindau protein