Casein kinase 1 regulates Sprouty2 in FGF-ERK signaling.
Sprouty2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase signaling, and is implicated as a tumor suppressor. SPRY2 inhibits FGF-RAS-ERK signaling by binding to growth factor receptor bound protein 2 (GRB2) during fibroblast growth factor receptor (FGFR) activation, disrupting the GRB2-SOS (son of sevenless) complex that transduces signals from FGFR to RAS. SPRY2 binding to GRB2 is modulated by phosphorylation but the key regulatory kinase(s) are not known. Prior studies identified the frequent presence of CK1 phosphorylation motifs on SPRY2. We therefore tested if CK1 has a role in SPRY2 phosphorylation and function. Loss of CK1 binding and inhibition of CK1 activity by two structurally distinct small molecules abrogated SPRY2 inhibition of FGF-ERK signaling, leading to decreased SPRY2 interaction with GRB2. Moreover, CK1 activity and binding are necessary for SPRY2 inhibition of FGF-stimulated neurite outgrowth in PC12 cells. Consistent with its proposed role as an inhibitor of FGF signaling, we find that CSNK1E transcript abundance negatively correlates with FGF1/FGF7 message in human gastric cancer samples. Modulation of CK1 activity may be therapeutically useful in the treatment of FGF/SPRY2-related diseases.
1] Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore [2] Signal Transduction Laboratory, Institute for Molecular and Cellular Biology, Biopolis, Singapore [3] Genome Institute of Singapore, Biopolis, Singapore.
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DG
Yim
Center for Computational Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
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S
Ghosh
Signal Transduction Laboratory, Institute for Molecular and Cellular Biology, Biopolis, Singapore.
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GR
Guy
1] Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore [2] Department of Biochemistry, YYL School of Medicine, National University of Singapore, Singapore, Singapore.
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Virshup
D000818:Animals; D047389:Casein Kinase I / Q000502:physiology*; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051380:GRB2 Adaptor Protein / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017468:Receptors, Fibroblast Growth Factor; C485561:SPRY2 protein, human; C404992:Spry2 protein, rat; D005346:Fibroblast Growth Factors; D047389:Casein Kinase I