UNC-51-like kinase regulation of fibroblast growth factor receptor substrate 2/3

Cell Signal. 2007 Jan;19(1):177-84. doi: 10.1016/j.cellsig.2006.06.003. Epub 2006 Aug 2.

Abstract

UNC-51-like kinases (ULK) are members of an evolutionarily conserved sub-family of ubiquitously expressed serine/threonine-specific protein kinases. Here we report that fibroblast growth factor receptor substrate (FRS) 2/3 are novel ULK2 carboxy-terminal domain interacting proteins. FRS2/3 are homologs that function as adaptor proteins to mediate signaling of multiple receptor tyrosine kinases. ULK2 interacts with the phospho-tyrosine binding (PTB) domain of FRS2/3. We demonstrate that siRNA targeting ULK2 in mouse P19 cells results in elevated FGFR1 mediated FRS3 and SHP2 tyrosyl phosphorylation. In addition, RNAi-mediated decrease in ULK2 causes increased interaction between FGFR1 and FRS3. ULK2 phosphorylates FRS2/3 in vitro, suggesting that ULK2 mediated phosphorylation may be a mechanism of FRS2/3 regulation. The data presented support a model in which ULK2, by interaction with FRS2/3 and inhibition of SynGAP, functions to negatively regulate tyrosyl phosphorylation of signaling proteins downstream of FGFR1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Autophagy-Related Protein-1 Homolog
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Signal Transduction
  • Two-Hybrid System Techniques
  • Tyrosine / metabolism
  • ras GTPase-Activating Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Frs3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Syngap1 protein, mouse
  • ras GTPase-Activating Proteins
  • Tyrosine
  • Ulk2 protein, mouse
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2
  • Autophagy-Related Protein-1 Homolog
  • Protein Serine-Threonine Kinases
  • Ulk1 protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse