A critical role for cortactin phosphorylation by Abl-family kinases in PDGF-induced dorsal-wave formation.
Proper regulation of cell morphogenesis and migration by adhesion and growth-factor receptors requires Abl-family tyrosine kinases [1-3]. Several substrates of Abl-family kinase have been identified, but they are unlikely to mediate all of the downstream actions of these kinases on cytoskeletal structure. We used a human protein microarray to identify the actin-regulatory protein cortactin as a novel substrate of the Abl and Abl-related gene (Arg) nonreceptor tyrosine kinases. Cortactin stimulates cell motility [4-6], and its upregulation in several cancers correlates with poor prognosis [7]. Even though cortactin can be tyrosine phosphorylated by Src-family kinases in vitro [8], we show that Abl and Arg are more adept at binding and phosphorylating cortactin. Importantly, we demonstrate that platelet-derived growth-factor (PDGF)-induced cortactin phosphorylation on three tyrosine residues requires Abl or Arg. Cortactin triggers F-actin-dependent dorsal waves in fibroblasts after PDGF treatment and thus results in actin reorganization and lamellipodial protrusion [9]. We provide evidence that Abl/Arg-mediated phosphorylation of cortactin is required for this PDGF-induced dorsal-wave response. Our results reveal that Abl-family kinases target cortactin as an effector of cytoskeletal rearrangements in response to PDGF.
Boyle
Scott N
SN
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Michaud
Gregory A
GA
Schweitzer
Barry
B
Predki
Paul F
PF
Koleske
Anthony J
AJ
D016475:3T3 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D051356:Cortactin / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D040081:Protein Array Analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D010982:Platelet-Derived Growth Factor; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D034281:Dynamins