ABL Tyrosine Kinases: Evolution of Function, Regulation, and Specificity

Colicelli, John

doi:10.1126/scisignal.3139re6

Cited by 312 publications

(353 citation statements)

References 239 publications

(273 reference statements)

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“…The only minor difference we observed was a slightly slower uptake in the dsDNA substrate balanced out by the faster clearance of the joint molecules, and resulting in the same rate and extent of the nicked circular product formation as the wild-type protein. These data are consistent with a sequential phosphorylation of RAD51 proposed earlier (55,56). According this this model, c-Abl phosphorylates RAD51 on Y315 by binding the consensus PXXP motif through its SH3 domain.…”

Section: Discussionsupporting

confidence: 79%

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Subramanyam

Ismail

Bhattacharya

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The DNA strand exchange protein RAD51 facilitates the central step in homologous recombination, a process fundamentally important for accurate repair of damaged chromosomes, restart of collapsed replication forks, and telomere maintenance. The active form of RAD51 is a nucleoprotein filament that assembles on single-stranded DNA (ssDNA) at the sites of DNA damage. The c-Abl tyrosine kinase and its oncogenic counterpart BCR-ABL fusion kinase phosphorylate human RAD51 on tyrosine residues 54 and 315. We combined biochemical reconstitutions of the DNA strand exchange reactions with total internal reflection fluorescence microscopy to determine how the two phosphorylation events affect the biochemical activities of human RAD51 and properties of the RAD51 nucleoprotein filament. By mimicking RAD51 tyrosine phosphorylation with a nonnatural amino acid, p-carboxymethyl-L-phenylalanine (pCMF), we demonstrated that Y54 phosphorylation enhances the RAD51 recombinase activity by at least two different mechanisms, modifies the RAD51 nucleoprotein filament formation, and allows RAD51 to compete efficiently with ssDNA binding protein RPA. In contrast, Y315 phosphorylation has little effect on the RAD51 activities. Based on our work and previous cellular studies, we propose a mechanism underlying RAD51 activation by c-Abl/BCR-ABL kinases.RAD51 recombinase | c-Abl tyrosine kinase | homologous recombination | single-molecule total internal reflection fluorescence microscopy | phosphorylation T he DNA in the human genome is constantly subjected to damage. This damage is a byproduct of normal cellular metabolism, exposure to radiation, and environmental mutagens (1). Homologous recombination (HR) and the pathways that use the machinery of HR are responsible for the accurate repair of the most deleterious DNA lesions, including double-stranded DNA breaks (DSBs), interstrand DNA cross-links, and damaged replication forks, and thereby contribute to maintenance of the stable genome (2-5). HR also plays an important role in telomere maintenance (6). HR, a process highly conserved throughout evolution, is carried out through a precisely coordinated and tightly regulated series of events. The key step in HR is the assembly of a RecA-family recombinase (phage UvsX, bacterial RecA, archaeal RadA, or eukaryotic RAD51) onto resected single-stranded DNA (ssDNA). The recombinase forms a nucleoprotein filament that then invades homologous duplex DNA, resulting in a displacement loop structure that can be used as a primer for synthesis using the intact duplex as a template. Similar to its bacterial and yeast homologs, the human RAD51 binds ssDNA in an ATP-dependent manner (7). The nucleoprotein filament formed by the ATP-bound RAD51 is arranged such that each RAD51 monomer binds three nucleotides, forming the pairing unit in these reactions (8). Beyond these basic attributes, the characteristics of human RAD51 protein differ significantly from its archaeal, bacterial, and yeast homologs.The critical role of HR requires all steps of this process ...

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Section: Discussionsupporting

confidence: 79%

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Subramanyam

Ismail

Bhattacharya

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In neurons and HEK293 cells, DAB1 enhances the kinase activity of FYN ( 13 ). In an analogy, we found that simultaneous expression of DAB1 and ABL1b, the major splice variant of ABL1 ( 11,12 ), increased the level of Tyr-phosphorylated ABL1b (pY-ABL1b) in a dose-dependent manner in RKO cells ( Fig. 3D ; compare lanes 4-6).…”

Section: Research Articlementioning

confidence: 58%

“…5H, lanes 2 and 4), but not Y2562F or Y2757F (lanes 3 and 5), markedly reduced the pY levels in the colorectal cancer cells. Notably, the aa sequence adjoining TRIO Y2681 has a strong similarity to the ABL target site consensus ( 11 ). It is also known that dTRIO protein binds to dABL ( 15 ).…”

Section: Apc/aesmentioning

confidence: 99%

Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO

et al. 2015

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We have recently identifi ed a metastasis suppressor gene for colorectal cancer: AES / Aes , which encodes an endogenous inhibitor of NOTCH signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1 / Dab1 . Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling-activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces RHOGEF activity and inhibits invasion of colorectal cancer cells. Importantly, TRIO pY2681 correlates with signifi cantly poorer prognosis of patients with colorectal cancer after surgery. SIGNIFICANCE:These results indicate that TRIO pY2681 is one of the downstream effectors of NOTCH signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. Cancer Discov; 5(2);[198][199][200][201][202][203][204][205][206][207][208][209][210][211]

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“…However, it is possible that the Hippo pathway prevents proliferation through other mechanisms as well. Although this study focused on the apoptotic role of c-Abl, c-Abl is also a pro-proliferative factor (reviewed in Sirvent et al 48 and Colicelli 49 ). Activation of c-Abl in the cytoplasm is involved in the response to growth factors [50][51][52] and F-actin assembly.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

et al. 2013

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The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.

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ABL Tyrosine Kinases: Evolution of Function, Regulation, and Specificity

Cited by 312 publications

References 239 publications

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

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