FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway.
Fibroblast growth factor (FGF) receptor substrate 2alpha (FRS2alpha) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12 cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PS/T of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.
Zhou
Wenchao
W
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Feng
Xiujing
X
Wu
Yingjie
Y
Benge
Johannes
J
Zhang
Zhe
Z
Chen
Zhengjun
Z
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D002070:Butadienes; C106534:FRS2 protein, human; D008565:Membrane Proteins; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3