Abstract
Mutations in the SH3PXD2B gene coding for the Tks4 protein are responsible for the autosomal recessive Frank-ter Haar syndrome. Tks4, a substrate of Src tyrosine kinase, is implicated in the regulation of podosome formation. Here, we report a novel role for Tks4 in the EGF signaling pathway. In EGF-treated cells, Tks4 is tyrosine-phosphorylated and associated with the activated EGF receptor. This association is not direct but requires the presence of Src tyrosine kinase. In addition, treatment of cells with LY294002, an inhibitor of PI 3-kinase, or mutations of the PX domain reduces tyrosine phosphorylation and membrane translocation of Tks4. Furthermore, a PX domain mutant (R43W) Tks4 carrying a reported point mutation in a Frank-ter Haar syndrome patient showed aberrant intracellular expression and reduced phosphoinositide binding. Finally, silencing of Tks4 was shown to markedly inhibit HeLa cell migration in a Boyden chamber assay in response to EGF or serum. Our results therefore reveal a new function for Tks4 in the regulation of growth factor-dependent cell migration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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COS Cells
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Cell Movement*
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Chlorocebus aethiops
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Chromones / pharmacology
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Craniofacial Abnormalities / genetics
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Craniofacial Abnormalities / metabolism*
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Craniofacial Abnormalities / mortality
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Developmental Disabilities / genetics
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Developmental Disabilities / metabolism
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Developmental Disabilities / mortality
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / metabolism*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Gene Silencing
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HeLa Cells
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Heart Defects, Congenital / genetics
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Heart Defects, Congenital / metabolism*
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Heart Defects, Congenital / mortality
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Humans
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Morpholines / pharmacology
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Mutation
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Osteochondrodysplasias / congenital*
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Osteochondrodysplasias / genetics
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Osteochondrodysplasias / metabolism
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Osteochondrodysplasias / mortality
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Structure, Tertiary
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Signal Transduction*
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Chromones
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Enzyme Inhibitors
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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SH3PXD2B protein, human
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Epidermal Growth Factor
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EGFR protein, human
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ErbB Receptors
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src-Family Kinases