Abl family kinases are central regulators of multiple cellular processes controlling actin dynamics, proliferation and differentiation. Recent studies indicate that different pathogens highjack Abl kinase signalling to reorganize the host actin cytoskeleton and promote the tyrosine phosphorylation of four known bacterial and viral effector proteins. Abl signalling is implicated in such diverse processes as microbial invasion, viral release from host cells, actin-based motility, actin-rich pedestal formation and cell scattering. Thus, Abl kinases are emerging as crucial regulators of multiple pathological signalling cascades during infection. Therapeutic intervention against Abl kinase activity might be an effective and novel strategy to combat serious microbial diseases.
"Presently, we have a good understanding of mechanisms involved in the activation of oncogenic tyrosine kinases, but little is known about cellular mechanisms involved in their inactivation. Considering that c-Abl tyrosine kinase has specific physiologically important repressive functions dependent on its kinase activation    , it is important that we aim at strategies that repress BCR-Abl and not c-Abl functions. Dephosphorylation of BCR-Abl, leading to its inactivation without affecting the activity of c-Abl is therefore a novel mechanism of downregulating the transforming property of this oncogene . "
[Show abstract][Hide abstract] ABSTRACT: The chimeric oncoprotein BCR-Abl exhibits deregulated protein tyrosine kinase activity and is responsible for the pathogenesis of certain human leukemias, such as chronic myelogenous leukemia. The activity of cellular Abl (c-Abl) and BCR-Abl are stringently regulated and the cellular mechanisms involved in their inactivation are poorly understood. Protein tyrosine phosphatases can negatively regulate Abl mediated signaling by dephosphorylating the kinase and/or its substrates. This study investigated the ability of the intracellular T cell protein tyrosine phosphatase (TCPTP/PTPN2) to dephosphorylate and regulate the functions of BCR-Abl and c-Abl. TCPTP is expressed as two alternately spliced isoforms - TC48 and TC45, which differ in their C-termini and localize to the cytoplasm and nucleus respectively. We show that TC48 dephosphorylates BCR-Abl but not c-Abl and inhibits its activity towards its substrate, CrkII. Y1127 and Y1294 residues whose phosphorylation corresponds with BCR-Abl activation status were the primary sites targeted by TC48. Co-localization and immunoprecipitaion experiments showed that TC48 interacted with BCR-Abl but not with c-Abl, and BCR domain was sufficient for interaction. TC48 expression resulted in stabilization of Bcr-Abl protein dependent on its phosphatase activity. Inactivation of cellular TC48 in K562 cells by stable expression of a dominant negative catalytically inactive mutant TC48, enhanced proliferation. TC48 expressing K562 clones showed reduced proliferation and enhanced sensitivity to STI571 compared to control clones suggesting that TC48 can repress the growth of CML cells. This study, identifies a novel cellular regulator that specifically inhibits the activity of oncogenic BCR-Abl but not that of the cellular Abl kinase.
"The c-abl−/− arg−/− double mutation, however, causes embryonic death with abnormalities in neuroepithelial cells and defects in neurulation . In addition, dysregulation of Abl leads to several pathological states; recent evidence suggests possible roles of Abl in breast-cancer invasiveness , neurological disorders , and microbial pathogenesis [29, 30]. "
[Show abstract][Hide abstract] ABSTRACT: Abl is a nonreceptor tyrosine kinase and plays an essential role in the modeling and remodeling of F-actin by transducing extracellular signals. Abl and its paralog, Arg, are unique among the tyrosine kinase family in that they contain an unusual extended C-terminal half consisting of multiple functional domains. This structural characteristic may underlie the role of Abl as a mediator of upstream signals to downstream signaling machineries involved in actin dynamics. Indeed, a group of SH3-containing accessory proteins, or adaptor proteins, have been identified that bind to a proline-rich domain of the C-terminal portion of Abl and modulate its kinase activity, substrate recognition, and intracellular localization. Moreover, the existence of signaling cascade and biological outcomes unique to each adaptor protein has been demonstrated. In this paper, we summarize functional roles and mechanisms of adaptor proteins in Abl-regulated actin dynamics, mainly focusing on a family of adaptor proteins, Abi. The mechanism of Abl's activation and downstream signaling mediated by Abi is described in comparison with those by another adaptor protein, Crk.
"Arg and its related kinase Abl are unique among cytoplasmic tyrosine kinases in that they contain not only the catalytic kinase domain, but also the actin-binding motifs in their carboxyl termini. In mammalian cell culture, Arg and Abl modulate a variety of F-actin-dependent processes, such as spreading and migration of fibroblasts and neurite extension of neuronal cells (Woodring et al., 2003; Hernandez et al., 2004; Backert et al., 2007). These kinases can be activated by PDGF, FGF and epidermal growth factor (EGF)/ErbB signals to control cell shape, membrane protrusions and cell motility (Zhu et al., 1993; Plattner et al., 1999, 2004; Schulze et al., 2005; Frasca et al., 2007; Yan et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Coordinated cell movements are crucial for vertebrate gastrulation and are controlled by multiple signals. Although many factors are shown to mediate non-canonical Wnt pathways to regulate cell polarity and intercalation during gastrulation, signaling molecules acting in other pathways are less investigated and the connections between various signals and cytoskeleton are not well understood. In this study, we show that the cytoplasmic tyrosine kinase Arg modulates gastrulation movements through control of actin remodeling. Arg is expressed in the dorsal mesoderm at the onset of gastrulation, and both gain- and loss-of-function of Arg disrupted axial development in Xenopus embryos. Arg controlled migration of anterior mesendoderm, influenced cell decision on individual versus collective migration, and modulated spreading and protrusive activities of anterior mesendodermal cells. Arg also regulated convergent extension of the trunk mesoderm by influencing cell intercalation behaviors. Arg modulated actin organization to control dynamic F-actin distribution at the cell-cell contact or in membrane protrusions. The functions of Arg required an intact tyrosine kinase domain but not the actin-binding motifs in its carboxyl terminus. Arg acted downstream of receptor tyrosine kinases to regulate phosphorylation of endogenous CrkII and paxillin, adaptor proteins involved in activation of Rho family GTPases and actin reorganization. Our data demonstrate that Arg is a crucial cytoplasmic signaling molecule that controls dynamic actin remodeling and mesodermal cell behaviors during Xenopus gastrulation.
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