title: Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate.
abstract: Protein-tyrosine kinase 6 (PTK6) is a non-myristoylated intracellular tyrosine kinase evolutionarily related to Src kinases. Aberrant PTK6 expression and intracellular localization have been detected in human prostate tumors. In the PC3 prostate cancer cell line, the pool of endogenous activated PTK6, which is phosphorylated on tyrosine residue 342, is localized at the membrane. Expression of ectopic membrane-targeted PTK6 led to dramatic morphology changes and formation of peripheral adhesion complexes in PC3 cells. Peripheral adhesion complex formation was dependent upon PTK6 kinase activity. We demonstrated that p130 CRK-associated substrate (p130CAS) is a novel direct substrate of PTK6, and it works as a crucial adapter protein in inducing peripheral adhesion complexes. Activation of ERK5 downstream of p130CAS was indispensable for this process. Knockdown of endogenous PTK6 led to reduced cell migration and p130CAS phosphorylation, whereas knockdown of p130CAS attenuated oncogenic signaling induced by membrane-targeted PTK6, including ERK5 and AKT activation. Expression of membrane-targeted PTK6 promoted cell migration, which could be impaired by knockdown of p130CAS or ERK5. Our study reveals a novel function for PTK6 at the plasma membrane and suggests that the PTK6-p130CAS-ERK5 signaling cascade plays an important role in cancer cell migration and invasion.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607. Electronic address: atyner@uic.edu.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050719:Crk-Associated Substrate Protein; D016023:Integrins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D017978:Receptors, Growth Factor; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D048054:Mitogen-Activated Protein Kinase 7
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