1. Schematic comparison of structural features of cell surface growth factor receptor tyrosine kinases and membrane-associated tyrosine kinase oncogene products. The cytoplasmic tyrosine kinase domain is represented in grey (src homology 1 or SH-1), and SH-2 and SH-3 domains are indicated. A: Ligand binding to the epidermal growth factor receptor (EGFR) promotes receptor dimerization, activation of the kinase, and transphosphorylation of the receptor cytoplasmic domain on tyrosine residues, which then interact with SH-2 domain containing substrates and elicit an intracellular signal. The N- and C-terminal deletions, in addition to point mutations within critical domains of the molecule, that activate v-erbB are illustrated. Autocrine production of TGFβ in cells that express the EGFR results in constitutive activation of the EGFR. B: A single point mutation in the transmembrane domain of the Neu/HER2 oncogene product is sufficient for ligand-independent activation. This mutation promotes receptor dimerization and kinase activation in the absence of ligand. Similarly, the loss of a single cysteine residue in the extracellular domain of the Ret receptor in multiple endocrine neoplasia type-2A syndrome results in a constitutively activated receptor. This mutation frees a cysteine residue that is normally involved in intrareceptor disulphide bond formation and enhances receptor dimerization presumably by the formation of intermolecular disulphide bonds promoting constitutive activation of the receptor catalytic activity. C: The gene rearrangements that activate the Met and Trk and Ret receptor-derived oncogene products. The majority of receptor oncogenes activated by gene rearrangement are fused with a protein domain capable of protein-protein interaction and thus mediate dimerization and constitutive activation of the kinase in the absence of ligand. D: The complex formed between CD4 and the Src family kinase Lck. The protein domains through which Lck and CD4 interact are represented as open boxes in these molecules. The c-Src kinase is maintained in an inactive conformation through the interaction of a negative regulatory phosphotyrosine residue in the C-terminus of c-Src with the Src SH-2 domain. The v-src oncogene is generated following deletion of this negative regulatory C-terminal tyrosine residue such that the kinase is now in an unconstrained conformation and is constitutively active. Following activation of many growth factor receptor tyrosine kinases, the c-Src SH-2 domain interacts with a phosphorylated tyrosine residue on the receptor with a greater affinity than its C-terminal phosphotyrosine residue (see Fig. 25-8). This relieves the negative regulation of c-Src and activates the kinase. EGF = epidermal growth factor; HGF/SF = hepatocyte growth factor-scatter factor; NGF = nerve growth factor; GDNF = glial cell derived nerve growth factor, TGFβ = transforming growth factor β.
Source: Oncogenes, The Online Metabolic and Molecular Bases of Inherited Disease
Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: Accessed: October 25, 2017
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