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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Animals
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Autophagy-Related Protein-1 Homolog
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Molecular Sequence Data
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / physiology*
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / metabolism
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
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Signal Transduction
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Two-Hybrid System Techniques
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Tyrosine / metabolism
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ras GTPase-Activating Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Frs3 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Syngap1 protein, mouse
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ras GTPase-Activating Proteins
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Tyrosine
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Ulk2 protein, mouse
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Fgfr2 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 2
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Autophagy-Related Protein-1 Homolog
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Protein Serine-Threonine Kinases
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Ulk1 protein, mouse
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse