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 bioc hemical signals that mediate ligand-independent transformation of cells by these transmembrane receptors are poorly defined. In this report, we demons trate that a constitutively activated mutant epidermal growth factor recept or (v-ErbB) induces the formation of a transformation-specific signaling mo dule that complexes with myosin II. The components:of this signaling comple x include the signal adapter proteins Shc, Grb2, and Nck, and tyrosine-phos phorylated forms of p21-activated kinase (Pak), caldesmon, and myosin light chain kinase. Transformation specific, tyrosine phosphorylation of Pak enh ances the catalytic activity of this serine/threonine kinase. Furthermore, the tyrosine phosphorylation of Pak is Rho-, but not Ras-, Rac-, or Cdc42-d ependent. These results demonstrate :that a ligand-independent epidermal gr owth factor receptor mutant can transduce oncogenic signals that are distin ct from ligand-dependent, mitogenic signals. In addition, these data provid e evidence for-the coupling of oncogenic receptor tyrosine kinases with the actomyosin molecular motor. This myosin-associated signaling module may me diate some of the biochemical changes of myosin found in v-ErbB-transformed fibroblasts, thereby contributing to the regulation of the mechanical forc es governing cellular adhesion, cytoskeletal tension, and, hence, anchorage -independent cell growth.