An oncogenic epidermal growth factor receptor signals via a p21-activated kinase-caldesmon-myosin phosphotyrosine complex.
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.
McManus
M J
MJ
Department of Biochemistry and Molecular Biology and the Tumor Biology Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
Boerner
J L
JL
Danielsen
A J
AJ
Wang
Z
Z
Matsumura
F
F
Maihle
N J
NJ
D000205:Actomyosin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015153:Blotting, Western; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain; D002448:Cell Adhesion; D002455:Cell Division; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002642:Chick Embryo; D002846:Chromatography, Affinity; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D005982:Glutathione Transferase / Q000378:metabolism; D008024:Ligands; D009154:Mutation; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D009218:Myosins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D018739:Oncogene Proteins v-erbB / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors; D014170:Transformation, Genetic; D014443:Tyrosine / Q000378:metabolism; D054462:p21-Activated Kinases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002148:Calmodulin-Binding Proteins; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D008024:Ligands; C078332:Nck protein; D015513:Oncogene Proteins; D018739:Oncogene Proteins v-erbB; D020033:Protein Isoforms; D011506:Proteins; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D000205:Actomyosin; D005982:Glutathione Transferase; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D009219:Myosin-Light-Chain Kinase; D009218:Myosins