Disease relevance of Abl2

• Family members Abl and Arg are catalytically activated upon Shigella infection, accumulate at the site of bacterial entry, and are required for efficient bacterial uptake, as internalization is blocked upon targeted deletion of these kinases or treatment with a specific pharmacological inhibitor [1].
• Phosphorylation by Arg also promotes p190RhoGAP's association with p120RasGAP and stimulates p190RhoGAP's ability to induce neuritogenesis in neuroblastoma cells [2].
• A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene [3].
• We also show that an Arg-to-Gln mutation in the PX domain of p47phox, which is found in patients with chronic granulomatous disease, eliminates phosphoinositide binding, as does the analogous mutation in the PX domain of p40phox [4].
• Achondroplasia has recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3), although the molecular consequences of this mutation have not been investigated [5].

High impact information on Abl2

• The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1 [6].
• The ls mice carry a point mutation of the EDN3 gene, which replaces the Arg residue at the C-terminus of the inactive intermediate big EDN3 with a Trp residue [7].
• We have sequenced the tyrosinase-related protein-1 cDNA encoded at this locus from Light mice and found that it contains a single base alteration from wild-type, causing an Arg to Cys change in the protein [8].
• Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly) [9].
• Comparative protein modeling and electrostatic calculations disclosed that mMCP-6 contains a prominent Lys/Arg-rich domain on its surface, distant from the active site [10].

Chemical compound and disease context of Abl2

• All mutation hotspots reported earlier in UVB-induced mouse squamous cell carcinomas (SCC) at codons 270 (Arg --> Cys), 149 (Pro --> Ser), 275 (Pro --> Leu and Pro --> Ser), and 176 (His --> Tyr) with a frequency of 32.1%, 7.1%, 14.7%, and 3.2% were detected in epidermal patches at a frequency 47.7%, 9.1%, 4.5%, and 2.3%, respectively [11].
• In a search for a basic carboxypeptidase that might work in concert with the major virulence factors, the Arg- and Lys-specific cysteine endoproteinases of Porphyromonas gingivalis, a novel 69.8-kDa metallocarboxypeptidase CPG70 was purified to apparent homogeneity from the culture fluid of P. gingivalis HG66 [12].
• We investigated comparatively the interactions of host cells with two types of rabies virus G protein, an avirulent type G (Gln) and a virulent type G (Arg) protein, having glutamine and arginine at position 333, respectively [13].
• Tryptase TC30 cleaved peptide substrates with Arg at the P1 position, and preferentially substrates with the Ser-Ile-Gin-Ser-Arg sequence corresponding to the HA cleavage site sequence of the A/PR/8/34 influenza virus [14].

Biological context of Abl2

• Here, we show that the related kinase Arg is activated downstream of PDGFRs in a manner dependent on Src family kinases and phospholipase C gamma1 (PLC-gamma1)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, as we showed previously for c-Abl [15].
• Functional interaction between the c-Abl and Arg protein-tyrosine kinases in the oxidative stress response [16].
• Mapping of Abll within a conserved linkage group on distal mouse chromosome 1 syntenic with human chromosome 1 using an interspecific cross [17].
• However, despite the generation of these mice over a decade ago, little is known regarding the mechanisms responsible for these phenotypes or the immune-related consequences of ablation of both the c-Abl and Arg kinases, which are coexpressed in lymphoid tissues [18].
• Our results demonstrate that p190RhoGAP is an Arg substrate in the developing brain and suggest that Arg mediates the adhesion-dependent regulation of neuronal morphogenesis in the postnatal brain by phosphorylating p190RhoGAP [2].

Anatomical context of Abl2

• Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton [19].
• We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium [19].
• The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system [19].
• The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion [20].
• c-Abl and the Abl-related gene product (Arg) are nonreceptor tyrosine kinases that regulate the actin cytoskeleton of cells by direct association with F-actin and localization to focal contacts [21].

Associations of Abl2 with chemical compounds

• PIP2, a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits the tyrosine kinase activities of both Arg and c-Abl in vitro and in cells [15].
• Because cationic Arg residues are determinants of Crp4 bactericidal peptide activity, we hypothesized that Asp and Glu residues in pro-Crp4(20-43) neutralize Crp4 Arg side chains in pro-Crp4(20-92) [22].
• The results show that the c-Abl SH3 domain binds directly to a proline-rich site (amino acids 567-576) in the Arg C-terminal region [16].
• Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function [19].
• We also show that pyrido[2,3-d]pyrimidine (PD) compounds, which inhibit Abl, Arg, and related kinases, block pedestal formation [23].

Enzymatic interactions of Abl2

• We now demonstrate that c-Abl and Arg form inducible complexes with and are phosphorylated by the PDGFR tyrosine kinase in vitro and in vivo [15].

Regulatory relationships of Abl2

• We show that c-Abl and Arg exhibit nonredundant functions downstream of the activated PDGFR [15].

Other interactions of Abl2

• Moreover, c-Abl and Arg, in turn, phosphorylate the PDGFR [15].
• Abll was mapped to mouse chromosome 1 by analysis of segregation with other distal chromosome 1 genetic polymorphisms by using a panel of DNAs from [(C3H/HeJ-gld/gld x Mus spretus) F1 x C3H/HeJ-gld/gld] interspecific backcross mice [17].
• ArgBP2, a multiple Src homology 3 domain-containing, Arg/Abl-interacting protein, is phosphorylated in v-Abl-transformed cells and localized in stress fibers and cardiocyte Z-disks [24].
• Two amino acid substitutions, Arg to His at amino acid 457 and Tyr to His at amino acid 469 of c-abl, modeled on mutations known to render v-src temperature-sensitive for tyrosine kinase activity, were introduced into p210BCR-ABL [25].

Analytical, diagnostic and therapeutic context of Abl2

• Mapping studies and sequence analysis have led to the identification of the CTD-ID that is highly conserved among the divergent C-terminal regions of Abl and Arg [26].
• The association of full-length Abl and Arg with EphB2 was confirmed by co-immunoprecipitation and found to involve several distinct protein interactions [27].
• Using indirect immunofluorescence, Arg was detected in the cytoplasm but not the nucleus of both transiently transfected COS cells and stable NIH3T3 transfectants [28].
• Using immunoelectron microscopy, we have localized Abl and Arg to the pre- and postsynaptic compartments of synapses in the mouse hippocampal area CA1 [29].
• Immunization with Arg 12 Ras led to disease-free survival in nine of 10 animals challenged with tumor cells containing an Arg 12 mutation, while no protection was afforded against tumors expressing other forms of Ras or other oncogenes [30].

References