Engineering the recruitment of phosphotyrosine binding domain-containing adaptor proteins reveals distinct roles for RET receptor-mediated cell survival

T. Kalle Lundgren, Rizaldy P. Scott, Matthew Smith, Tony Pawson, Patrik Ernfors*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)29886-29896
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number40
DOIs
StatePublished - Oct 6 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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