| Structural highlights
Disease
[ABL1_HUMAN] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Function
[ABL1_HUMAN] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov State Models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures, but evident in a retrospective analysis of Lilly in-house structures: the X-ray structure of Abl with WHI-P154. Using MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states.
Predicting the Conformational Variability of Abl tyrosine kinase using Molecular Dynamics Simulations and Markov State Models.,Meng Y, Gao C, Clawson DK, Atwell S, Russell M, Vieth M, Roux B J Chem Theory Comput. 2018 Feb 23. doi: 10.1021/acs.jctc.7b01170. PMID:29474075[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yuan ZM, Huang Y, Ishiko T, Kharbanda S, Weichselbaum R, Kufe D. Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1437-40. PMID:9037071
- ↑ Han L, Wong D, Dhaka A, Afar D, White M, Xie W, Herschman H, Witte O, Colicelli J. Protein binding and signaling properties of RIN1 suggest a unique effector function. Proc Natl Acad Sci U S A. 1997 May 13;94(10):4954-9. PMID:9144171
- ↑ Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Kharbanda S, Wang R, Sung P, Shinohara A, Weichselbaum R, Kufe D. Regulation of Rad51 function by c-Abl in response to DNA damage. J Biol Chem. 1998 Feb 13;273(7):3799-802. PMID:9461559
- ↑ Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature. 1999 Jun 24;399(6738):809-13. PMID:10391250 doi:10.1038/21697
- ↑ Kitao H, Yuan ZM. Regulation of ionizing radiation-induced Rad52 nuclear foci formation by c-Abl-mediated phosphorylation. J Biol Chem. 2002 Dec 13;277(50):48944-8. Epub 2002 Oct 11. PMID:12379650 doi:10.1074/jbc.M208151200
- ↑ Yoshida K, Komatsu K, Wang HG, Kufe D. c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage. Mol Cell Biol. 2002 May;22(10):3292-300. PMID:11971963
- ↑ Sanguinetti AR, Mastick CC. c-Abl is required for oxidative stress-induced phosphorylation of caveolin-1 on tyrosine 14. Cell Signal. 2003 Mar;15(3):289-98. PMID:12531427
- ↑ Tani K, Sato S, Sukezane T, Kojima H, Hirose H, Hanafusa H, Shishido T. Abl interactor 1 promotes tyrosine 296 phosphorylation of mammalian enabled (Mena) by c-Abl kinase. J Biol Chem. 2003 Jun 13;278(24):21685-92. Epub 2003 Apr 2. PMID:12672821 doi:10.1074/jbc.M301447200
- ↑ Grossmann AH, Kolibaba KS, Willis SG, Corbin AS, Langdon WS, Deininger MW, Druker BJ. Catalytic domains of tyrosine kinases determine the phosphorylation sites within c-Cbl. FEBS Lett. 2004 Nov 19;577(3):555-62. PMID:15556646 doi:10.1016/j.febslet.2004.10.054
- ↑ Perkinton MS, Standen CL, Lau KF, Kesavapany S, Byers HL, Ward M, McLoughlin DM, Miller CC. The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate Fe65/amyloid precursor protein nuclear signaling. J Biol Chem. 2004 May 21;279(21):22084-91. Epub 2004 Mar 18. PMID:15031292 doi:10.1074/jbc.M311479200
- ↑ Hu H, Bliss JM, Wang Y, Colicelli J. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Curr Biol. 2005 May 10;15(9):815-23. PMID:15886098 doi:10.1016/j.cub.2005.03.049
- ↑ Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D. c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem. 2005 Mar 25;280(12):11147-51. Epub 2005 Jan 18. PMID:15657060 doi:10.1074/jbc.M413787200
- ↑ Tanos B, Pendergast AM. Abl tyrosine kinase regulates endocytosis of the epidermal growth factor receptor. J Biol Chem. 2006 Oct 27;281(43):32714-23. Epub 2006 Aug 29. PMID:16943190 doi:10.1074/jbc.M603126200
- ↑ Liu X, Huang W, Li C, Li P, Yuan J, Li X, Qiu XB, Ma Q, Cao C. Interaction between c-Abl and Arg tyrosine kinases and proteasome subunit PSMA7 regulates proteasome degradation. Mol Cell. 2006 May 5;22(3):317-27. PMID:16678104 doi:10.1016/j.molcel.2006.04.007
- ↑ Boyle SN, Michaud GA, Schweitzer B, Predki PF, Koleske AJ. A critical role for cortactin phosphorylation by Abl-family kinases in PDGF-induced dorsal-wave formation. Curr Biol. 2007 Mar 6;17(5):445-51. Epub 2007 Feb 15. PMID:17306540 doi:10.1016/j.cub.2007.01.057
- ↑ Sossey-Alaoui K, Li X, Cowell JK. c-Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration. J Biol Chem. 2007 Sep 7;282(36):26257-65. Epub 2007 Jul 9. PMID:17623672 doi:10.1074/jbc.M701484200
- ↑ Xiong X, Cui P, Hossain S, Xu R, Warner B, Guo X, An X, Debnath AK, Cowburn D, Kotula L. Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1. Biochim Biophys Acta. 2008 May;1783(5):737-47. doi: 10.1016/j.bbamcr.2008.01.028., Epub 2008 Feb 15. PMID:18328268 doi:10.1016/j.bbamcr.2008.01.028
- ↑ Yogalingam G, Pendergast AM. Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J Biol Chem. 2008 Dec 19;283(51):35941-53. doi: 10.1074/jbc.M804543200. Epub 2008, Oct 21. PMID:18945674 doi:10.1074/jbc.M804543200
- ↑ Fernow I, Tomasovic A, Siehoff-Icking A, Tikkanen R. Cbl-associated protein is tyrosine phosphorylated by c-Abl and c-Src kinases. BMC Cell Biol. 2009 Nov 5;10:80. doi: 10.1186/1471-2121-10-80. PMID:19891780 doi:10.1186/1471-2121-10-80
- ↑ Michael M, Vehlow A, Navarro C, Krause M. c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis. Curr Biol. 2010 May 11;20(9):783-91. doi: 10.1016/j.cub.2010.03.048. Epub 2010, Apr 22. PMID:20417104 doi:10.1016/j.cub.2010.03.048
- ↑ Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs WH 3rd, Treiber DK, Patel HK, Zarrinkar PP, Lockhart DJ, Sawyers CL, Kuriyan J. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res. 2006 Jan 15;66(2):1007-14. PMID:16424036 doi:http://dx.doi.org/66/2/1007
- ↑ Wojcik J, Hantschel O, Grebien F, Kaupe I, Bennett KL, Barkinge J, Jones RB, Koide A, Superti-Furga G, Koide S. A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain. Nat Struct Mol Biol. 2010 Apr;17(4):519-27. Epub 2010 Mar 28. PMID:20357770 doi:10.1038/nsmb.1793
- ↑ Meng Y, Gao C, Clawson DK, Atwell S, Russell M, Vieth M, Roux B. Predicting the Conformational Variability of Abl tyrosine kinase using Molecular Dynamics Simulations and Markov State Models. J Chem Theory Comput. 2018 Feb 23. doi: 10.1021/acs.jctc.7b01170. PMID:29474075 doi:http://dx.doi.org/10.1021/acs.jctc.7b01170
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