Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases

Abstract

The F-actin cytoskeleton is a fundamental component of all eukaryotic cells. It provides force and stability and plays an integral role in a diverse array of cellular processes. The spatiotemporal regulation of F-actin dynamics is essential for proper biological output. The basic molecular machinery underlying the assembly and disassembly of filamentous actin is conserved in all eukaryotic cells. Additionally, protein tyrosine kinases, found only in multicellular eukaryotes, provide links between extracellular signals and F-actin-dependent cellular processes. Among the tyrosine kinases, c-Abl and its relative Arg are unique in binding directly to F-actin. Recent results have demonstrated a role for c-Abl in membrane ruffling, cell spreading, cell migration, and neurite extension in response to growth factor and extracellular matrix signals. c-Abl appears to regulate the assembly of F-actin polymers into different structures, depending on the extracellular signal. Interestingly, c-Abl contains nuclear import and export signals, and the nuclear c-Abl inhibits differentiation and promotes apoptosis in response to genotoxic stress. The modular structure and the nuclear-cytoplasmic shuttling of c-Abl suggest that it integrates multiple signals to coordinate F-actin dynamics with the cellular decision to differentiate or to die.

F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death

“…Among the molecular modulators of cytoskeletal organization are the Abl family tyrosine kinases c-Abl and Arg (Abl1 and Abl2) that regulate actin dynamics by phosphorylating cytoskeletal proteins and through direct F-actin binding (Woodring et al, 2003;Hernandez et al, 2004). In addition to a catalytic domain, they possess SH3-, SH2-and actin-binding domains (Pendergast, 2002).…”

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

“…Several studies have shown that c-Abl contains intramolecular interactions that provide autoinhibitory mechanisms (Pendergast, 2002;Pluk et al, 2002;Hantschel et al, 2003). Studies have also found that c-Abl kinase activity is regulated by intermolecular interactions with negative regulators, which include Bcr (Liu et al, 1996;Ling et al, 2003), PAG (Wen and Van Etten, 1997) and F-actin (Woodring et al, 2003).…”

Nucleo-cytoplasmic communication in apoptotic response to genotoxic and inflammatory stress

“…The ubiquitously expressed Abl tyrosine kinase is a transducer of a variety of cell extrinsic and intrinsic signals including those from growth factors, cell adhesion, oxidative stress and DNA damage [10,11]. The Abl protein contains three nuclear localization signals (NLS), Fig.…”

“…The N-terminal region of Abl resembles the Src-family of tyrosine kinases and adopts an auto-inhibited conformation assembled through intramolecular interactions among its SH3-SH2-kinase domains [13,14]. The C-terminal region of Abl contains subcellular location cues, including NLS, NES, binding sites for G-actin, F-actin and binding site for DNA [10,11]. We have shown that F-actin, but not G-actin, is an allosteric inhibitor of Abl tyrosine kinase [15].…”

“…F-actin functions as a "coinhibitor", enforcing or stabilizing the "auto-inhibited" conformation to inhibit Abl kinase activity [14]. The cytoplasmic Abl tyrosine kinase regulates F-actin dynamics in response to growth factors and cell adhesion [10].…”