title: Dynamic phosphorylation of tyrosine 665 in pseudopodium-enriched atypical kinase 1 (PEAK1) is essential for the regulation of cell migration and focal adhesion turnover.
abstract: Pseudopodium-enriched atypical kinase 1 (PEAK1) is a recently described tyrosine kinase that associates with the actin cytoskeleton and focal adhesion (FA) in migrating cells. PEAK1 is known to promote cell migration, but the responsible mechanisms remain unclear. Here, we show that PEAK1 controls FA assembly and disassembly in a dynamic pathway controlled by PEAK1 phosphorylation at Tyr-665. Knockdown of endogenous PEAK1 inhibits random cell migration. In PEAK1-deficient cells, FA lifetimes are decreased, FA assembly times are shortened, and FA disassembly times are extended. Phosphorylation of Tyr-665 in PEAK1 is essential for normal PEAK1 localization and its function in the regulation of FAs; however, constitutive phosphorylation of PEAK1 Tyr-665 is also disruptive of its function, indicating a requirement for precise spatiotemporal regulation of PEAK1. Src family kinases are required for normal PEAK1 localization and function. Finally, we provide evidence that PEAK1 promotes cancer cell invasion through Matrigel by a mechanism that requires dynamic regulation of Tyr-665 phosphorylation.
authors.affiliation: Department of Pathology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Bristow
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Reno
authors.forename: Minji
authors.initials: M
authors.lastname: Jo
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klemke
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D022001:Focal Adhesions / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D007797:Laminin / Q000737:chemistry; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D011509:Proteoglycans / Q000737:chemistry; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D051419:Paxillin; D011509:Proteoglycans; C059485:matrigel; D014443:Tyrosine; D003094:Collagen; C573947:PEAK1 protein, human; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases