Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 40, Pages 29886-29896Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M600473200
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The RET receptor tyrosine kinase is important for several different biological functions during development. The recruitment at the phosphorylated Tyr1062 site in RET of a number of different phosphotyrosine binding ( PTB) domain-containing adaptor proteins, including Shc and Frs2, plays a dominant role for the multiple different biological functions of the RET receptor during development, including stimulation of cell survival. Here, we demonstrate that a competitive recruitment of Shc as opposed to Frs2 mediates the survival signaling arising from RET activation. Based on results from a peptide array, we have genetically engineered the PTB domain binding site of RET to rewire its recruitment of the PTB proteins Shc and Frs2. An engineered RET that has a competitive interaction with Shc at the expense of Frs2, but not a RET receptor that only recruits Frs2, activates cell survival signaling pathways and is protective from cell death in neuronal SK- N- MC cells. Thus, cell type- specific functions involve a competitive recruitment of different PTB adaptor molecules by RET that activate selective signaling pathways.
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