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Abl protein, and this requires the FABD and an intact SH2 domain (P. J. Woodring, S. A. Johnson, K. Shah et al., unpublished).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.

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