Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RET proto-oncogene encodes a member of the receptor tyrosine kinase family. Multiple endocrine neoplasia type 2B (MEN 2B) is caused by the mutation of a conserved methionine to a threonine in the catalytic domain of the RET kinase. When the MEN 2B point mutation was introduced into the epidermal growth factor (EGF) receptor (M857T EGFR), the intrinsic tyrosine kinase activity of the mutant receptor was similar to that of wild-type EGF receptor and remained ligand-dependent. However, the mutant receptor showed an enhanced transforming capacity compared to the wild-type receptor as judged by its ability to mediate the growth of NIH 3T3 cells in soft agar. Using the oriented peptide library approach to examine substrate specificity, the M857T mutation was found to be associated with a decrease in the selectivity of the receptor for Phe and an increase in the selectivity for acidic residues at the P + 1 position as compared to wild-type EGF receptor. Short-term responses to EGF were similar in cells expressing wild-type and M857T EGF receptors. However, significant differences in receptor down-regulation were observed between the two receptors. These data demonstrate that the MEN 2B point mutation alters the substrate specificity of receptor tyrosine kinases and suggest that the enhanced oncogenesis associated with the MEN 2B mutation may be due in part to alterations in receptor regulation.
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PMID:The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor. 862 56

Control of cell growth and differentiation occurs via extracellular signals known as growth factors. Growth factors are high affinity ligands for transmembrane receptors belonging to the family of receptor tyrosine kinases (RTKs). A number of genetic evidences have implicated RTKs in human diseases including developmental disorders and cancer. For instance, germline missense mutations involving the Ret receptor are found in patients affected by multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) or familial medullary thyroid carcinomas. Somatic mutations in the Kit receptor are found in mastocytomas and in gastrointestinal tumors. Germline and sporadic mutations of the Met receptor have been described in kidney and hepatocellular carcinomas. Overexpression of the HER-2/neu receptor in breast cancer has been associated with tumor progression. The enzymatic activity of RTKs is strictly regulated and is usually inhibited under basal conditions. Receptor activation triggers a biochemical signalling cascade inside the cytoplasm, named signal transduction, which is subverted during the malignant transformation of cells. Signal transduction by RTKs is a multistep process which includes: (i) Ligand binding and receptor dimerization, (ii) receptor phosphorylation on tyrosine residues; (iii) recruitment to the receptor and activation of cytoplasmic signaling molecules that transmit signals to the nucleus. Each of the steps involved in this process can potentially be targeted to block the aberrant properties of tyrosine kinase receptors. By using the MET oncogene as a model this review focuses on the strategies that can be applied to therapeutically target RTKs.
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PMID:Receptor tyrosine kinases as therapeutic targets: the model of the MET oncogene. 1146 38