Abstract
The polarised distribution of signals downstream from receptor tyrosine kinases (RTKs) regulates fundamental cellular processes that control cell migration, growth and morphogenesis. It is poorly understood how RTKs are involved in the localised signalling and actin remodelling required for these processes. Here, we show that the Gab1 scaffold is essential for the formation of a class of polarised actin microdomain, namely dorsal ruffles, downstream from the Met, EGF and PDGF RTKs. Gab1 associates constitutively with the actin-nucleating factor N-WASP. Following RTK activation, Gab1 recruits Nck, an activator of N-WASP, into a signalling complex localised to dorsal ruffles. Formation of dorsal ruffles requires interaction between Gab1 and Nck, and also requires functional N-WASP. Epithelial cells expressing Gab1DeltaNck (Y407F) exhibit decreased Met-dependent Rac activation, fail to induce dorsal ruffles, and have impaired cell migration and epithelial remodelling. These data show that a Gab1-Nck signalling complex interacts with several RTKs to promote polarised actin remodelling and downstream biological responses.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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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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Binding Sites
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Cell Line
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Cell Surface Extensions / drug effects
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Cell Surface Extensions / enzymology*
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Enzyme Activation / drug effects
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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ErbB Receptors / metabolism
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Hepatocyte Growth Factor / pharmacology
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Humans
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Mice
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Models, Biological
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Molecular Sequence Data
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Oncogene Proteins / chemistry
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Oncogene Proteins / metabolism*
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Phosphoproteins / metabolism*
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Protein Binding / drug effects
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-crk / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptors, Platelet-Derived Growth Factor / metabolism
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Tyrosine / metabolism
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Wiskott-Aldrich Syndrome Protein, Neuronal / metabolism
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rac GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Gab1 protein, mouse
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Nck protein
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Oncogene Proteins
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Phosphoproteins
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Proto-Oncogene Proteins c-crk
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Wiskott-Aldrich Syndrome Protein, Neuronal
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Tyrosine
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Hepatocyte Growth Factor
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ErbB Receptors
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PDGF receptor tyrosine kinase
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Receptor Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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rac GTP-Binding Proteins