Abstract
Many ligand-independent receptor tyrosine kinases are tumorigenic. The biochemical signals that mediate ligand-independent transformation of cells by these transmembrane receptors are poorly defined. In this report, we demonstrate that a constitutively activated mutant epidermal growth factor receptor (v-ErbB) induces the formation of a transformation-specific signaling module that complexes with myosin II. The components of this signaling complex include the signal adapter proteins Shc, Grb2, and Nck, and tyrosine-phosphorylated forms of p21-activated kinase (Pak), caldesmon, and myosin light chain kinase. Transformation-specific, tyrosine phosphorylation of Pak enhances the catalytic activity of this serine/threonine kinase. Furthermore, the tyrosine phosphorylation of Pak is Rho-, but not Ras-, Rac-, or Cdc42-dependent. These results demonstrate that a ligand-independent epidermal growth factor receptor mutant can transduce oncogenic signals that are distinct from ligand-dependent, mitogenic signals. In addition, these data provide evidence for the coupling of oncogenic receptor tyrosine kinases with the actomyosin molecular motor. This myosin-associated signaling module may mediate some of the biochemical changes of myosin found in v-ErbB- transformed fibroblasts, thereby contributing to the regulation of the mechanical forces governing cellular adhesion, cytoskeletal tension, and, hence, anchorage-independent cell growth.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actomyosin / metabolism
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Blotting, Western
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Calmodulin-Binding Proteins / genetics
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Calmodulin-Binding Proteins / metabolism*
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Catalysis
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Catalytic Domain
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Cell Adhesion
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Cell Division
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Cell Line, Transformed
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Cells, Cultured
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Chick Embryo
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Chromatography, Affinity
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Cytoskeleton / metabolism
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Down-Regulation
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Electrophoresis, Polyacrylamide Gel
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ErbB Receptors / chemistry
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Fibroblasts / metabolism
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GRB2 Adaptor Protein
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Glutathione Transferase / metabolism
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Ligands
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Mutation
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Myosin-Light-Chain Kinase / genetics
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Myosin-Light-Chain Kinase / metabolism*
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Myosins / chemistry
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Myosins / genetics
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Myosins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Oncogene Proteins v-erbB / chemistry
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Oncogene Proteins v-erbB / genetics
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Oncogene Proteins v-erbB / metabolism*
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Phosphorylation
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Precipitin Tests
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Protein Binding
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Protein Isoforms
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Proteins / genetics
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Proteins / metabolism
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Rats
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Recombinant Fusion Proteins / metabolism
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Shc Signaling Adaptor Proteins
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Signal Transduction
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Time Factors
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Transformation, Genetic
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Tyrosine / metabolism
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p21-Activated Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Calmodulin-Binding Proteins
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GRB2 Adaptor Protein
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Grb2 protein, rat
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Ligands
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Nck protein
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Oncogene Proteins
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Oncogene Proteins v-erbB
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Protein Isoforms
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Proteins
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Recombinant Fusion Proteins
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Shc Signaling Adaptor Proteins
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Shc1 protein, rat
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Tyrosine
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Actomyosin
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Glutathione Transferase
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ErbB Receptors
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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Myosin-Light-Chain Kinase
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Myosins