title: Abl2/Abl-related gene stabilizes actin filaments, stimulates actin branching by actin-related protein 2/3 complex, and promotes actin filament severing by cofilin.
abstract: Both Arp2/3 complex and the Abl2/Arg nonreceptor tyrosine kinase are essential to form and maintain diverse actin-based structures in cells, including cell edge protrusions in fibroblasts and cancer cells and dendritic spines in neurons. The ability of Arg to promote cell edge protrusions in fibroblasts does not absolutely require kinase activity, raising the question of how Arg might modulate actin assembly and turnover in the absence of kinase function. Arg has two distinct actin-binding domains and interacts physically and functionally with cortactin, an activator of the Arp2/3 complex. However, it was not known whether and how Arg influences actin filament stability, actin branch formation, or cofilin-mediated actin severing or how cortactin influences these reactions of Arg with actin. Arg or cortactin bound to actin filaments stabilizes them from depolymerization. Low concentrations of Arg and cortactin cooperate to stabilize filaments by slowing depolymerization. Arg stimulates formation of actin filament branches by Arp2/3 complex and cortactin. An Arg mutant lacking the C-terminal calponin homology actin-binding domain stimulates actin branch formation by the Arp2/3 complex, indicative of autoinhibition. ArgΔCH can stimulate the Arp2/3 complex even in the absence of cortactin. Arg greatly potentiates cofilin severing of actin filaments, and cortactin attenuates this enhanced severing. The ability of Arg to stabilize filaments, promote branching, and increase severing requires the internal (I/L)WEQ actin-binding domain. These activities likely underlie important roles that Arg plays in the formation, dynamics, and stability of actin-based cellular structures.
authors.affiliation: From the Departments of Molecular, Cellular and Developmental Biology and.
authors.forename: Naomi
authors.initials: N
authors.lastname: Courtemanche
authors.affiliation: the Departments of Molecular Biophysics and Biochemistry and.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Gifford
authors.affiliation: the Departments of Molecular Biophysics and Biochemistry and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: From the Departments of Molecular, Cellular and Developmental Biology and the Departments of Molecular Biophysics and Biochemistry and Cell Biology, Yale University, New Haven, Connecticut 06511 and thomas.pollard@yale.edu.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Pollard
authors.affiliation: the Departments of Molecular Biophysics and Biochemistry and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520 Neurobiology and anthony.koleske@yale.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D051377:Actin-Related Protein 2; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D051338:Cofilin 1 / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D051377:Actin-Related Protein 2; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D051338:Cofilin 1; D051356:Cortactin; D001120:Arginine; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases
keywords: Actin; Arp2/3 Complex; Cofilin; Cortactin; Tyrosine-protein Kinase (Tyrosine Kinase)