An Oncogenic Epidermal Growth Factor Receptor Signals via a p21-activated Kinase-Caldesmon-Myosin Phosphotyrosine Complex

• Published in: The Journal of biological chemistry Vol. 275; no. 45; pp. 35328 - 35334
• Main Authors: McManus, Michael J., Boerner, Julie L., Danielsen, Andrew J., Wang, Ze, Matsumura, Fumio, Maihle, Nita J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.11.2000; American Society for Biochemistry and Molecular Biology
• Subjects: Actomyosin - metabolism; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Blotting, Western; caldesmon; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; Catalysis; Catalytic Domain; Cell Adhesion; Cell Division; Cell Line, Transformed; Cells, Cultured; Chick Embryo; Chromatography, Affinity; Cytoskeleton - metabolism; Down-Regulation; Electrophoresis, Polyacrylamide Gel; ErbB Receptors - chemistry; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fibroblasts - metabolism; Glutathione Transferase - metabolism; GRB2 Adaptor Protein; Grb2 protein; Ligands; Mutation; myosin; Myosin-Light-Chain Kinase - genetics; Myosin-Light-Chain Kinase - metabolism; Myosins - chemistry; Myosins - genetics; Myosins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncogene Proteins v-erbB - chemistry; Oncogene Proteins v-erbB - genetics; Oncogene Proteins v-erbB - metabolism; p21-Activated Kinases; Pak protein; Phosphorylation; Precipitin Tests; Protein Binding; Protein Isoforms; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins - genetics; Proteins - metabolism; Rats; Recombinant Fusion Proteins - metabolism; Shc Signaling Adaptor Proteins; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 1; Time Factors; Transformation, Genetic; Tyrosine - metabolism; v-ErbB-2 gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M005399200

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.