title: Enhancement of ABL kinase catalytic efficiency by a direct binding regulator is independent of other regulatory mechanisms.
abstract: ABL family tyrosine kinases are tightly regulated by autoinhibition and phosphorylation mechanisms. These kinases maintain an inactive conformation through intramolecular interactions involving SH3 and SH2 domains. RIN1, a downstream effector of RAS, binds to the ABL SH3 and SH2 domains and stimulates ABL tyrosine kinase activity. RIN1 binding to the ABL2 kinase resulted in a large decrease in Km and a small increase in Vmax toward an ABL consensus substrate peptide. The enzyme efficiency (k(cat)/Km) was increased more than 5-fold by RIN1. In addition, RIN1 strongly enhanced ABL-mediated phosphorylation of CRK, PSTPIP1, and DOK1, all established ABL substrates but with unique protein structures and distinct target sequences. Importantly RIN1-mediated stimulation of ABL kinase activity was independent of activation by SRC-mediated phosphorylation. RIN1 increased the kinase activity of both ABL1 and ABL2, and this occurred in the presence or absence of ABL regulatory domains outside the SH3-SH2-tyrosine kinase domain core. We further demonstrate that a catalytic site mutation associated with broad drug resistance, ABL1T315I, remains responsive to stimulation by RIN1. These findings are consistent with an allosteric kinase activation mechanism by which RIN1 binding promotes a more accessible ABL catalytic site through relief of autoinhibition. Direct disruption of RIN1 binding may therefore be a useful strategy to suppress the activity of normal and oncogenic ABL, including inhibitor-resistant mutants that confound current therapeutic strategies. Stimulation through derepression may be applicable to many other tyrosine kinases autoinhibited by coupled SH3 and SH2 domains.
authors.affiliation: Department of Biological Chemistry, Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cao
authors.forename: Keith Q
authors.initials: KQ
authors.lastname: Tanis
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
authors.forename: John
authors.initials: J
authors.lastname: Colicelli
mesh_terms: D000818:Animals; D002384:Catalysis; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D018411:Spodoptera; D013379:Substrate Specificity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C092117:RIN1 protein, human; D016315:Proto-Oncogene Proteins c-abl
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