| Structural highlights
Function
[ABL1_MOUSE] 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-191' 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.
Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).,Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J Cancer Res. 2002 Aug 1;62(15):4236-43. PMID:12154025[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Feller SM, Knudsen B, Hanafusa H. c-Abl kinase regulates the protein binding activity of c-Crk. EMBO J. 1994 May 15;13(10):2341-51. PMID:8194526
- ↑ Mayer BJ, Hirai H, Sakai R. Evidence that SH2 domains promote processive phosphorylation by protein-tyrosine kinases. Curr Biol. 1995 Mar 1;5(3):296-305. PMID:7780740
- ↑ Kharbanda S, Pandey P, Jin S, Inoue S, Bharti A, Yuan ZM, Weichselbaum R, Weaver D, Kufe D. Functional interaction between DNA-PK and c-Abl in response to DNA damage. Nature. 1997 Apr 17;386(6626):732-5. PMID:9109492 doi:10.1038/386732a0
- ↑ Kain KH, Klemke RL. Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk-CAS complexes. J Biol Chem. 2001 May 11;276(19):16185-92. Epub 2001 Jan 19. PMID:11279004 doi:10.1074/jbc.M100095200
- ↑ Kumar S, Bharti A, Mishra NC, Raina D, Kharbanda S, Saxena S, Kufe D. Targeting of the c-Abl tyrosine kinase to mitochondria in the necrotic cell death response to oxidative stress. J Biol Chem. 2001 May 18;276(20):17281-5. Epub 2001 Feb 28. PMID:11350980 doi:10.1074/jbc.M101414200
- ↑ Zambrano N, Bruni P, Minopoli G, Mosca R, Molino D, Russo C, Schettini G, Sudol M, Russo T. The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cells expressing a constitutively active form of the Abl protoncogene. J Biol Chem. 2001 Jun 8;276(23):19787-92. Epub 2001 Feb 21. PMID:11279131 doi:10.1074/jbc.M100792200
- ↑ Cong F, Tang J, Hwang BJ, Vuong BQ, Chu G, Goff SP. Interaction between UV-damaged DNA binding activity proteins and the c-Abl tyrosine kinase. J Biol Chem. 2002 Sep 20;277(38):34870-8. Epub 2002 Jul 9. PMID:12107171 doi:10.1074/jbc.M204416200
- ↑ Tanis KQ, Veach D, Duewel HS, Bornmann WG, Koleske AJ. Two distinct phosphorylation pathways have additive effects on Abl family kinase activation. Mol Cell Biol. 2003 Jun;23(11):3884-96. PMID:12748290
- ↑ Plattner R, Koleske AJ, Kazlauskas A, Pendergast AM. Bidirectional signaling links the Abelson kinases to the platelet-derived growth factor receptor. Mol Cell Biol. 2004 Mar;24(6):2573-83. PMID:14993293
- ↑ Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G. c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration. FEBS Lett. 2010 Jan 4;584(1):15-21. doi: 10.1016/j.febslet.2009.11.009. Epub . PMID:19903482 doi:10.1016/j.febslet.2009.11.009
- ↑ O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. PMID:19878872 doi:10.1016/j.ccr.2009.09.028
- ↑ Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002 Aug 1;62(15):4236-43. PMID:12154025
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