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Gene Review

Abl1  -  c-abl oncogene 1, non-receptor tyrosine...

Mus musculus

Synonyms: AI325092, Abelson murine leukemia viral oncogene homolog 1, Abelson tyrosine-protein kinase 1, Abl, E430008G22Rik, ...
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Disease relevance of Abl1


High impact information on Abl1

  • For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes [6].
  • The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML [4].
  • The c-Abl protein is a non-receptor tyrosine kinase involved in many aspects of mammalian development. c-Abl kinase is widely expressed, but high levels are found in hyaline cartilage in the adult, bone tissue in newborn mice, and osteoblasts and associated neovasculature at sites of endochondrial ossification in the fetus [7].
  • Mice homozygous for mutations in the gene encoding c-Abl (AIM) display increased perinatal mortality, reduced fertility, foreshortened crania and defects in the maturation of B cells in bone marrow [7].
  • Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation [7].

Chemical compound and disease context of Abl1


Biological context of Abl1

  • This suggests a key role for these factors, and perhaps for c-Abl itself, in the regulated activation of Ig light chain gene rearrangement [13].
  • Moreover, MuSK and Abl kinases effected reciprocal tyrosine phosphorylation and formed a complex after agrin engagement [14].
  • These results indicate that Abl inhibits cell proliferation by interacting with central elements of the cell cycle control apparatus in the nucleus, and suggest a direct connection between p53 and Rb in this growth-inhibitory pathway [15].
  • A clue to its normal function is suggested by overexpression of Abl in fibroblasts, which leads to inhibition of cell growth [15].
  • Using a quantitative transfection assay, we show that both c-Abl and transforming Abl proteins inhibit entry into S phase and this effect is absolutely dependent on nuclear localization [15].

Anatomical context of Abl1


Associations of Abl1 with chemical compounds

  • Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib [1].
  • v-Abl is an oncogenic form of the c-Abl nonreceptor tyrosine kinase. v-Abl induces transcription of c-myc, and c-Myc function is a necessary but not sufficient component of the v-Abl transformation program [17].
  • Nuclear localization of Abl can be directed by a pentalysine nuclear localization signal in the Abl C-terminus [15].
  • These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl/p73 pathway [18].
  • In this study, we show that c-Abl mediates a second pathway by which adhesion to extracellular matrix regulates cell killing by chemotherapeutic agents 5-arabinofuranosylcytosine, cisplatin, and camptothecin [18].
  • Ectopic expression of CrkII, a Rac activator that is inactivated by Abl-mediated tyrosine phosphorylation, antagonizes Abl-mediated dorsal membrane localization of RacV12 [19].

Physical interactions of Abl1

  • DNA microarray analyses enabled us to identify two genes inhibited by v-Abl that encode the Igk 3' enhancer-binding transcription factors Spi-B and IRF-4 [13].
  • 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 [20].
  • An Abl mutant which no longer binds p53 does not enhance p53 transcriptional activity and fails to suppress growth [21].
  • The catalytic activity of c-Abl tyrosine kinase is reduced in fibroblasts that are detached from the extracellular matrix [22].
  • Here we demonstrate that c-Abl interacts constitutively with DNA-PK [23].

Enzymatic interactions of Abl1

  • c-Abl phosphorylates Dok1 to promote filopodia during cell spreading [16].
  • In vitro evidence indicates that DNA-dependent protein kinase (DNA-PK) can also phosphorylate and thus potentially activate Abl kinase activity in response to IR exposure [24].
  • The transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl [25].
  • We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites [26].
  • We also found that vinexin alpha but not beta was phosphorylated at tyrosine residue when c-Abl or v-Abl was co-expressed [27].

Regulatory relationships of Abl1

  • Filopodia are dynamic F-actin structures that cells use to explore their environment. c-Abl tyrosine kinase promotes filopodia during cell spreading through an unknown mechanism that does not require Cdc42 activity [16].
  • These results support a model where c-Abl is inhibited in part through an intramolecular Src homology 3-linker interaction and stimulated to full catalytic activity by sequential phosphorylation at Tyr-412 and Tyr-245 [28].
  • We find that a construct encoding the first two Src homology 3 (SH3) domains of the Src homology 2/SH3 adaptor protein Nck can activate c-Abl in human 293T cells [29].
  • The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-beta receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis [30].
  • GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins [31].

Other interactions of Abl1

  • Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts [16].
  • Further, we demonstrate that the Abl cytostatic effect requires both the Rb and p53 tumor suppressor gene products [15].
  • 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 [30].
  • These data show that, although both kinases are activated and form complexes with proteins in the PDGFR signaling pathway, only c-Abl functions downstream of PLC-gamma1 to mediate chemotaxis [30].
  • In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate [32].
  • Second, the c-Abl effects on insulin signaling are not observed in cells devoid of FAK (FAK(-/-) cells) [33].

Analytical, diagnostic and therapeutic context of Abl1


  1. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Kerkelä, R., Grazette, L., Yacobi, R., Iliescu, C., Patten, R., Beahm, C., Walters, B., Shevtsov, S., Pesant, S., Clubb, F.J., Rosenzweig, A., Salomon, R.N., Van Etten, R.A., Alroy, J., Durand, J.B., Force, T. Nat. Med. (2006) [Pubmed]
  2. Mutation of a phenylalanine conserved in SH3-containing tyrosine kinases activates the transforming ability of c-Abl. Jackson, P.K., Paskind, M., Baltimore, D. Oncogene (1993) [Pubmed]
  3. cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: role in vascular hypertrophy. Ushio-Fukai, M., Zuo, L., Ikeda, S., Tojo, T., Patrushev, N.A., Alexander, R.W. Circ. Res. (2005) [Pubmed]
  4. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Hu, Y., Liu, Y., Pelletier, S., Buchdunger, E., Warmuth, M., Fabbro, D., Hallek, M., Van Etten, R.A., Li, S. Nat. Genet. (2004) [Pubmed]
  5. Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells. Oki, S., Limnander, A., Danial, N.N., Rothman, P.B. Blood (2002) [Pubmed]
  6. B cell signaling and tumorigenesis. Jumaa, H., Hendriks, R.W., Reth, M. Annu. Rev. Immunol. (2005) [Pubmed]
  7. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Li, B., Boast, S., de los Santos, K., Schieren, I., Quiroz, M., Teitelbaum, S.L., Tondravi, M.M., Goff, S.P. Nat. Genet. (2000) [Pubmed]
  8. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Fiskus, W., Pranpat, M., Bali, P., Balasis, M., Kumaraswamy, S., Boyapalle, S., Rocha, K., Wu, J., Giles, F., Manley, P.W., Atadja, P., Bhalla, K. Blood (2006) [Pubmed]
  9. Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution. Cheng, W.H., von Kobbe, C., Opresko, P.L., Fields, K.M., Ren, J., Kufe, D., Bohr, V.A. Mol. Cell. Biol. (2003) [Pubmed]
  10. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Golas, J.M., Arndt, K., Etienne, C., Lucas, J., Nardin, D., Gibbons, J., Frost, P., Ye, F., Boschelli, D.H., Boschelli, F. Cancer Res. (2003) [Pubmed]
  11. Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. Mishra, S., Zhang, B., Cunnick, J.M., Heisterkamp, N., Groffen, J. Cancer Res. (2006) [Pubmed]
  12. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). La Rosée, P., Corbin, A.S., Stoffregen, E.P., Deininger, M.W., Druker, B.J. Cancer Res. (2002) [Pubmed]
  13. A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. Muljo, S.A., Schlissel, M.S. Nat. Immunol. (2003) [Pubmed]
  14. Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction. Finn, A.J., Feng, G., Pendergast, A.M. Nat. Neurosci. (2003) [Pubmed]
  15. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. Wen, S.T., Jackson, P.K., Van Etten, R.A. EMBO J. (1996) [Pubmed]
  16. c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. Woodring, P.J., Meisenhelder, J., Johnson, S.A., Zhou, G.L., Field, J., Shah, K., Bladt, F., Pawson, T., Niki, M., Pandolfi, P.P., Wang, J.Y., Hunter, T. J. Cell Biol. (2004) [Pubmed]
  17. Induction of c-myc transcription by the v-Abl tyrosine kinase requires Ras, Raf1, and cyclin-dependent kinases. Zou, X., Rudchenko, S., Wong, K., Calame, K. Genes Dev. (1997) [Pubmed]
  18. Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl. Truong, T., Sun, G., Doorly, M., Wang, J.Y., Schwartz, M.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  19. Abl tyrosine kinase promotes dorsal ruffles but restrains lamellipodia extension during cell spreading on fibronectin. Jin, H., Wang, J.Y. Mol. Biol. Cell (2007) [Pubmed]
  20. Functional interaction between the c-Abl and Arg protein-tyrosine kinases in the oxidative stress response. Cao, C., Leng, Y., Li, C., Kufe, D. J. Biol. Chem. (2003) [Pubmed]
  21. p53 dependent growth suppression by the c-Abl nuclear tyrosine kinase. Goga, A., Liu, X., Hambuch, T.M., Senechal, K., Major, E., Berk, A.J., Witte, O.N., Sawyers, C.L. Oncogene (1995) [Pubmed]
  22. Inhibition of c-Abl tyrosine kinase activity by filamentous actin. Woodring, P.J., Hunter, T., Wang, J.Y. J. Biol. Chem. (2001) [Pubmed]
  23. Functional interaction between DNA-PK and c-Abl in response to DNA damage. Kharbanda, S., Pandey, P., Jin, S., Inoue, S., Bharti, A., Yuan, Z.M., Weichselbaum, R., Weaver, D., Kufe, D. Nature (1997) [Pubmed]
  24. Regulation of DNA-dependent protein kinase activity by ionizing radiation-activated abl kinase is an ATM-dependent process. Shangary, S., Brown, K.D., Adamson, A.W., Edmonson, S., Ng, B., Pandita, T.K., Yalowich, J., Taccioli, G.E., Baskaran, R. J. Biol. Chem. (2000) [Pubmed]
  25. STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells. Sillaber, C., Gesbert, F., Frank, D.A., Sattler, M., Griffin, J.D. Blood (2000) [Pubmed]
  26. Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase. Liedtke, M., Pandey, P., Kumar, S., Kharbanda, S., Kufe, D. Oncogene (1998) [Pubmed]
  27. Abl kinase interacts with and phosphorylates vinexin. Mitsushima, M., Takahashi, H., Shishido, T., Ueda, K., Kioka, N. FEBS Lett. (2006) [Pubmed]
  28. c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. Brasher, B.B., Van Etten, R.A. J. Biol. Chem. (2000) [Pubmed]
  29. Activation of the Abl tyrosine kinase in vivo by Src homology 3 domains from the Src homology 2/Src homology 3 adaptor Nck. Smith, J.M., Katz, S., Mayer, B.J. J. Biol. Chem. (1999) [Pubmed]
  30. Bidirectional signaling links the Abelson kinases to the platelet-derived growth factor receptor. Plattner, R., Koleske, A.J., Kazlauskas, A., Pendergast, A.M. Mol. Cell. Biol. (2004) [Pubmed]
  31. The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways. Voss, J., Posern, G., Hannemann, J.R., Wiedemann, L.M., Turhan, A.G., Poirel, H., Bernard, O.A., Adermann, K., Kardinal, C., Feller, S.M. Oncogene (2000) [Pubmed]
  32. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. Kuribara, R., Honda, H., Matsui, H., Shinjyo, T., Inukai, T., Sugita, K., Nakazawa, S., Hirai, H., Ozawa, K., Inaba, T. Mol. Cell. Biol. (2004) [Pubmed]
  33. Role of c-Abl in directing metabolic versus mitogenic effects in insulin receptor signaling. Frasca, F., Pandini, G., Malaguarnera, R., Mandarino, A., Messina, R.L., Sciacca, L., Belfiore, A., Vigneri, R. J. Biol. Chem. (2007) [Pubmed]
  34. c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis. Furstoss, O., Dorey, K., Simon, V., Barilà, D., Superti-Furga, G., Roche, S. EMBO J. (2002) [Pubmed]
  35. c-Abl regulates early growth response protein (EGR1) in response to oxidative stress. Stuart, J.R., Kawai, H., Tsai, K.K., Chuang, E.Y., Yuan, Z.M. Oncogene (2005) [Pubmed]
  36. Aph2, a protein with a zf-DHHC motif, interacts with c-Abl and has pro-apoptotic activity. Li, B., Cong, F., Tan, C.P., Wang, S.X., Goff, S.P. J. Biol. Chem. (2002) [Pubmed]
  37. Identification of a candidate human spectrin Src homology 3 domain-binding protein suggests a general mechanism of association of tyrosine kinases with the spectrin-based membrane skeleton. Ziemnicka-Kotula, D., Xu, J., Gu, H., Potempska, A., Kim, K.S., Jenkins, E.C., Trenkner, E., Kotula, L. J. Biol. Chem. (1998) [Pubmed]
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