Proteins recruited to RTKs include enzymes, such as phospholipase C Navitoclax purchase and phosphatidylinositol 3 kinase, and adaptor proteins, including growth factor receptor bound protein 2 and Src homology colla gen proteins. These latter proteins contain multiple protein protein interactions motifs. The resulting complex relays and amplifies an exquisitely fine tuned regulation of multiple downstream signaling events, which de pending on cellular context, mediate specific biological responses. This regulation is perturbed in cancers, including those of intestinal epithelial cell origin such as colorectal cancer. Deregulation of RTKs in CRC commonly involves the over expression of the receptor and or its ligand.
As il lustrated by the Met hepatocyte growth factor and epidermal growth factor receptor signaling axis, this dysregulation often takes place at the earliest stages of the disease and it is observed in virtually all metastatic CRC. Ligand or receptor deregulation may result in a lower threshold for growth Inhibitors,Modulators,Libraries factor stimulation, autocrine paracrine ligand receptor activation loops, and even ligand independent constitu tive receptor activation. Regardless of the mechanisms of RTK oncogenic activation, the outcome is the loss of the normally fine tuned regulation of downstream signaling, which may ultimately contribute to the acquisition of cancer properties. Notably, its has been shown that the expression of constitutively activated forms of the Met receptor in non transformed IECs promoted morpho logical transformation, enhanced proliferation rate, in duced loss of both growth contact inhibition and anchorage dependent growth, and increased in vivo an giogenic, tumorigenic, and metastatic capacities.
Studies performed predominantly in fibroblast and breast cancer cell models have revealed that Grb2 and Shc adaptor proteins are among the signaling proteins that, upon Inhibitors,Modulators,Libraries recruitment by activated RTKs, mediate events directly linked to the initiation and progression of cancer. Many RTKs interact directly with Grb2, some rely on Shc family adaptors Inhibitors,Modulators,Libraries to recruit Grb2, and others do both. While direct Grb2 RTK interactions involve binding of the Grb2 SH2 domain to pYXNX mo tifs, Shc proteins interact with RTKs primarily through the binding of their N terminal PTB domain to NPXpY motifs. The latter results in phosphorylation Inhibitors,Modulators,Libraries of Tyr resi dues within the Shc central collagen homology domain 1.
These phosphorylated tyrosine residues consti tute consensus binding sites for the Grb2 SH2 domain, thus allowing Shc to engage Grb2 driven signaling path ways. The Inhibitors,Modulators,Libraries best characterized role of the Vandetanib mechanism of action two adaptor proteins, Grb2 and Shc, is to link RTKs to the activation of the Ras Raf MEK Erk mitogenic pathway. The constitutive association of the N terminal Grb2 SH3 domain with the Ras guanine nucleotide exchange factor, Son of Sevenless con stitutes one component of this connection.
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