mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins.
Murine Sprouty2 (mSpry2) is a conserved ortholog of Drosophila Sprouty, a gene that inhibits several tyrosine kinase receptor pathways, resulting in net reduction of mitogen-activated protein (MAP) kinase activation. However, the precise mechanism mediating mSpry2 function as a negative regulator in tyrosine kinase growth factor pathways that regulate diverse biological functions remains incompletely characterized. Fibroblast growth factor 10 (FGF10) is a key positive regulator of lung branching morphogenesis and induces epithelial expression of mSpry2 adjacent to mesenchymal sites of FGF10. Herein, we demonstrate that FGF10 stimulation of mouse lung epithelial cells (MLE15) overexpressing mSpry2 results in both mSpry2 tyrosine phosphorylation and differential binding of mSpry2 to several key upstream target proteins in the MAP kinase-activating pathway. Thus FGF receptor (FGFR) activation results in increased association of mSpry2 with growth factor receptor-binding protein 2, suc-1-associated nuerotrophic factor target 2, and Raf but decreased binding to protein tyrosine phosphatase 2 and GTPase-activating protein 1, resulting in a net reduction of MAP kinase activation. mSpry2 also spatially translocates to the plasma membrane and intracellular membrane structures in response to FGF10 stimulation. Our data demonstrate novel intracellular mechanisms mediating mSpry2 function as a negative regulator of uncontrolled FGF-induced MAP kinase signaling.
Tefft
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Center for Craniofacial Biology, Department of Surgery, and the Developmental Biology Program, The Childrens Hospital Los Angeles Research Institute, University of Southern California Schools of Dentistry and Medicine, 90023, USA.
Lee
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M
Smith
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Crowe
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DL
Bellusci
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Warburton
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D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C404992:Spry2 protein, rat; D014443:Tyrosine; D005346:Fibroblast Growth Factors; C052888:fibroblast growth factor (1-10)