Structure and Dynamic Regulation of Abl Kinases*

Abstract

The c-abl proto-oncogene encodes a unique protein-tyrosine kinase (Abl) distinct from c-Src, c-Fes, and other cytoplasmic tyrosine kinases. In normal cells, Abl plays prominent roles in cellular responses to genotoxic stress as well as in the regulation of the actin cytoskeleton. Abl is also well known in the context of Bcr-Abl, the oncogenic fusion protein characteristic of chronic myelogenous leukemia. Selective inhibitors of Bcr-Abl, of which imatinib is the prototype, have had a tremendous impact on clinical outcomes in chronic myelogenous leukemia and revolutionized the field of targeted cancer therapy. In this minireview, we focus on the structural organization and dynamics of Abl kinases and how these features influence inhibitor sensitivity. Structural Overview of the c-Abl Kinase CoreThe kinase core of the c-Abl protein has a domain organization similar to that of the Src family kinases, with sequential Src homology (SH) 3 3 and SH2 domains, an SH2/kinase linker, and a bilobed kinase domain (Fig. 1). This core is flanked by an N-terminal "cap" (N-cap) region with a signal sequence for myristoylation, which serves dual roles in regulation of kinase activity and in membrane localization. C-terminal to the kinase domain is a long region of Ͼ600 amino acids encoded by a single exon, which controls interaction of Abl with other SH3-containing proteins and the actin cytoskeleton. This region also regulates nuclear-cytoplasmic shuttling of the kinase (1-4). These key structural and regulatory features are discussed in detail below. The Myristoylated N-cap Is Critical for Down-regulation of AblThe N-cap is ϳ80 amino acids in length and is myristoylated in the 1b splice variant of Abl (5). The first crystal structure of the Abl core (residues 1-531) revealed that this N-terminal myristic acid group binds a deep hydrophobic pocket in the C-terminal lobe (C-lobe) of the kinase domain ( Fig. 1) (6). Binding of the myristoyl group into this pocket induces a bend in C-lobe helix ␣I, allowing the SH2 domain to dock onto the C-lobe of the kinase domain (Fig. 2). Interaction of the myristoylated N-cap with the C-lobe is critical to maintenance of the autoinhibited state, as mutation of the myristoylation signal sequence results in a highly active kinase (7). Interestingly, small molecules that bind to this site also modulate kinase activity, supporting an allosteric connection between this regulatory pocket and the kinase active site (8 -11).In addition to binding the C-lobe of the kinase domain, the N-cap also influences kinase regulation via the SH3 and SH2 domains. Although the N-cap region was disordered in the first crystal structure of the c-Abl core, a more recent structure with a modified N-cap revealed that Ser 69 (numbered according to Protein Data Bank (PDB) code 2FO0) 4 is phosphorylated and contacts the short connector joining the SH3 and SH2 domains. Mutation of Ser 69 increased Abl activity, identifying this site as a potential input for regulatory kinases (12). Additional contacts were observed between N...

Phosphorylation of Tip60 Tyrosine 327 by Abl Kinase Inhibits HAT Activity through Association with FE65

“…The c-Abl proto-oncogene encodes a unique protein-tyrosine kinase (Abl) which is distinct from other cytoplasmic tyrosine kinases [11, 12]. In normal cells, Abl functions in cellular responses to genotoxic stress as well as regulation of the actin cytoskeleton [13].…”

Fusion Gene BCR-Abl : From Etiopathogenesis to the Management of Chronic Myeloid Leukemia

“…If there are no stimuli, then the activity of ALB gene kinase would not occur. 16,26 This is due the presence of autoinhibition mechanism by myristoyl group located at Ncap ABL region. Myristoyl are able to pull the C lobe of kinase domain, thus binding the SH2 and SH3 to kinase domain.…”

“…Therefore, deletion or mutation of Ncap, SH2 domain, and or SH3 domain would increase kinase activity. 16,26 In BCR-ABL fusion gene, ABL Ncap region did not join BCR gene (Figure 3), thus autoinhibition mechanism did not occur. The merging of BCR with ABL would cause autophosphorilation in BCR-ABL kinase protein, causing an increase of kinase protein activity.…”

“…The merging of BCR with ABL would cause autophosphorilation in BCR-ABL kinase protein, causing an increase of kinase protein activity. 26 This event would affect various protein and adaptor molecule inside cells to bind into BCR-ABL protein and activating various intracellular signaling pathway 3 . Figure 3.…”

“…3,26 Therefore, tretment in which BCR-ABL is the target, wouldd contribute in inhibiting the activity of tirosin kinase, so-called Tyrosine Kinase Inhibitor (TKI). An instance of TKI is imatinib.…”