Peptide corresponding to amino acids 425 to 439 of human p62dok (1).
Signals from most growth factors and cytokines are transduced by receptor tyrosine kinases or non-receptor tyrosine kinases. Activated tyrosine kinases phosphorylate their substrates, which mediate the cellular response to extracellular stimuli. A long-sought major substrate termed p62dok (downstream of tyrosine kinase) for many tyrosine kinases including c-kit, v-abl, v-Fps, v-Src, v-Fms, and activated EGF, PDGF, IGF, VEGF and insulin receptors was identified recently from human and mouse by several laboratories. Upon phosphorylation, p62dok forms a complex with the ras GTPase-activating protein (RasGAP). p62dok represents a new family with very recently identified p56dok. Human DOK1 is a 481 amino acid protein.
Docking proteins are substrates of tyrosine kinases and function in the recruitment and assembly of specific signal transduction molecules. Here we found that p62dok family members act as substrates for the c-Ret receptor tyrosine kinase. In addition to dok-1, dok-2, and dok-3, two new family members, dok-4 and dok-5 have been identified that can directly associate with Y1062 of c-Ret. Dok-4 and dok-5 constitute a subgroup of dok family members that is coexpressed with c-Ret in various neuronal tissues. Activated c-Ret promotes neurite outgrowth of PC12 cells; for this activity, Y1062 in c-Ret is essential. c-Ret/dok fusion proteins, in which Y1062 of c-Ret is deleted and replaced by the sequences of dok-4 or dok-5, induce ligand-dependent axonal outgrowth of PC12 cells, whereas a c-Ret fusion containing dok-2 sequences does not elicit this response. Dok-4 and dok-5 do not associate with rasGAP or Nck, in contrast to p62dok and dok-2. Moreover, dok-4 and dok-5 enhance c-Ret-dependent activation of mitogen-activated protein kinase.
