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doi: 10.1242/10.1242/jcs.00622

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

¹ The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037-1099, USA
² Division of Biological Sciences, Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA

View larger version (26K): [in a new window]   Fig. 1. Modular domains in the Abl family of tyrosine kinases. The extreme N-terminus of the c-Abl protein contains a variable region (V, light and dark gray), which in some family members contains a Cap region (dark gray) and/or a consensus motif for N-terminal myristoylation (Myr-). The Src homology-3 domain (SH3, yellow), Src homology-2 domain (SH2, green) and the catalytic domain (Kinase, dark blue) make up the remaining N-terminal half of c-Abl. In the C-terminal half there are four PXXPXK/R sequences (light blue), three nuclear localization sequences (NLS, black), one nuclear export sequence (NES, light green) and three high mobility group-like boxes (HLB, white). In addition, at the extreme C-terminus there is an actin-binding domain (Actin-BD), which contains a region that mediates binding to monomeric actin (G, pink) and a consensus motif that mediates binding to filamentous actin (F, orange). The regulatory Y245 and Y412 are indicated as red circles. The sequence conservation for these domains, regions and residues in other members of the Abl family is depicted here (in some cases not yet supported experimentally). The oncogenic forms of Abl contain modified N-termini: v-Abl contains a viral gag sequence and Bcr-Abl contains the N-terminal portion of the breakpoint cluster region protein, as labeled. Unique to Drosophila Abl is a consensus motif for binding to EVH1 domains (EFPPPPXD, purple) and unique to Arg is an additional C-terminal F-actin binding region (F-actin-BD 2).

View larger version (36K): [in a new window]   Fig. 2. Proposed mechanisms for the regulation of c-Abl tyrosine kinase. The crystal structure of the N-terminal region of c-Abl suggests it is folded into an inactive conformation through three intramolecular interactions: (1) Myr-CAP interaction with the C-lobe of the kinase domain; (2) SH3 interaction with the SH2-CAT linker; and (3) placement of the activation loop in such a way that hinders substrate entry. The C-terminus and the Cap are depicted with dotted lines, because the position of these regions was not elucidated in the current c-Abl crystal structure. The inactive conformation may involve the C-terminal region. For example, we have found F-actin to inhibit purified Abl protein, and this requires the FABD and an intact SH2 domain (P. J. Woodring, S. A. Johnson, K. Shah et al., unpublished). Binding of F-actin may further enforce the inactive conformation. Disruption of the inactive conformation can be achieved by several mechanisms (bottom). For example, the Myr-Cap may be unlatched through membrane binding. SH3 or SH2 ligands may unclamp the kinase domain from the SH3-SH2 regulatory domains. Proteins with SH3 domains that bind to the Abl PXXP motifs may also activate Abl (Table 1). Phosphorylation of Y245 in the SH2-CAT linker and Y412 in the activation loop may stabilize the active conformation. PDGF-dependent stimulation of c-Abl requires Src and PLC-. Src can phosphorylate Y412 whereas PLC- is proposed to reduce the level of PtdIns(4,5)P2 to activate c-Abl. Cell-adhesion-mediated activation of c-Abl is dependent on mechanisms that override the negative effect of F-actin on the kinase. Importantly, the FABD is required to keep Abl in the inactive conformation in detached cells. Once activated, c-Abl phosphorylates substrate proteins to regulate various F-actin-based processes, such as membrane ruffling, filopodial exploration, neurite extension and cell migration.