The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

ALK  -  anaplastic lymphoma receptor tyrosine kinase

Homo sapiens

Synonyms: ALK tyrosine kinase receptor, Anaplastic lymphoma kinase, CD246, NBLST3
 ten Berge,  Poort-Keesom,  Meijer,  Willemze,  Meijer,  von Mensdorff-Pouilly,  Snijdewint,  Hilgers,  Oudejans,  Raetz,  Carroll,  Schooler,  Perkins,  Virshup,  Carlson,  Maes,  Wlodarska,  de Wolf-Peeters,  Peeters,  Cools,  Vanhentenrijk,  Marynen,  Bonvini,  Rosolen,  Falini,  Gastaldi,  Elenitoba-Johnson,  Lim,  Coffin,  Schumacher,  Crockett,  Jenson,  Rockwood,  Pulford,  Roncador,  Biddolph,  Jones,  Mason,  Delsol, Philipp B. Staber, Helmut Bergler, Claudia Fuchs, Werner Linkesch, David W. Sternberg, Silvia Schauer, Gerald Hoefler, Isabella Bambach, Veronika Sexl, Wilhelm G. Dirks, Marshall E. Kadin, Andelko Hrzenjak, Naznin Haq, Kotaro Funato, Lukas Kenner, Paul Vesely, Rene G. Ott, Carmen J. Tartari, Arianna Donella-Deana, Rosalind H. Gunby, Carlo Gambacorti-Passerini, Barbara Cimbro, Roberta Sottocornola, Leonardo Scapozza, Addolorata M. L. Coluccia, Lorenzo A. Pinna, Robert C. Doebele, Amanda B. Pilling, Dara L. Aisner, Tatiana G. Kutateladze, Anh T. Le, Andrew J. Weickhardt, Kimi L. Kondo, Derek J. Linderman, Lynn E. Heasley, Wilbur A. Franklin, Marileila Varella-Garcia, D. Ross Camidge, D. Ross Camidge, Scott A. Kono, Antonella Flacco, Aik-Choon Tan, Robert C. Doebele, Qing Zhou, Lucio Crino, Wilbur A. Franklin, Marileila Varella-Garcia, Kengo Takeuchi, Shuji Takada, Sakae Okumura, Ken Nakagawa, Toshihide Ueno, Manabu Soda, Young Lim Choi, Yuki Togashi, Yoshihiro Yamashita, Yukitoshi Satoh, Yuichi Ishikawa, Kentaro Inamura, Satoko Hatano, Hiroyuki Mano,  Lai,  Rassidakis,  Fujio,  Medeiros,  Amin,  Ramdas,  Kunisada,  Cutler,  Gilles,  Goy,  
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of ALK


High impact information on ALK


Chemical compound and disease context of ALK


Biological context of ALK

  • These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells [12].
  • Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis [19].
  • All such cases result from a novel fusion created by the ALK gene on chromosome 2p23 and NPM on 5q35 or other variant translocation partners [20].
  • Down-regulation of Bcl-XL significantly reduced the antiapoptotic potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human ALCL-derived KARPAS-299 cells [21].
  • NPM/ALK kinase activity was required to promote Bcl-XL expression and its protective effect on mitochondrial homeostasis [21].

Anatomical context of ALK

  • A rare variant of diffuse large B-cell lymphoma (DLBCL), originally described in 1997, was thought to overexpress full-length ALK in contrast to a chimeric protein characteristic of ALCL [20].
  • In agreement, Src-kinase inhibitors or pp60(c-src) siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines [22].
  • The CLTCL gene is constitutively expressed in lymphoid cells and therefore presumably contributes an active promoter for the CLTCL-ALK gene [14].
  • Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors [19].
  • The distinctive granular cytoplasmic staining pattern for ALK was likely to be due to binding of the fusion protein to clathrin-coated vesicles [14].

Associations of ALK with chemical compounds

  • However, full-length ALK protein lacks tyrosine kinase activity and thus the mechanism of oncogenesis has remained elusive [20].
  • We have studied the effect of 17-allylamino,17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin, on NPM-ALK steady-state level in ALCL cells [23].
  • Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT [24].
  • To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin [25].
  • Our data support that JSI-124 is a potentially useful therapeutic agent for ALK+ ALCL [15].
  • Mutation of the first and second (FFY), first and third (FYF), or all three (FFF) tyrosine residues impaired both kinase activity and transforming ability of NPM/ALK [26].
  • Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers [27].
  • The particular ALK fusion expressed may have an impact on protein stability and sensitivity to crizotinib, and this may underlie the heterogeneity in responses observed in the clinic [28].

Physical interactions of ALK

  • We describe 6 cases of ALK+ DLBCL characterized by a simple or complex t(2;17)(p23;q23) involving the clathrin gene (CLTC) at chromosome band 17q23 and the ALK gene at chromosome band 2p23 [20].
  • Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM [29].

Enzymatic interactions of ALK

  • ALK is phosphorylated independently of a direct interaction of PTN with ALK [30].

Regulatory relationships of ALK


Other interactions of ALK

  • Moreover, these results demonstrate the presence of CLTC-ALK fusions in these tumors and extend the list of diseases associated with this genetic abnormality to include classical T-cell or null ALCL, ALK+ DLBCL, and inflammatory myofibroblastic tumors [20].
  • A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation [35].
  • Here we have identified TRK-fused gene (TFG) as a new ALK partner in 2 ALCL, 1 of which exhibited a t(2;3)(p23;q21) [2].
  • In conclusion, STAT3 directly contributes to the high level of TIMP1 expression in ALK(+) ALCL, and TIMP1 expression correlates with high level of STAT3 activation in ALCL [31].
  • Other rearrangements involving the ALK gene have recently been shown to be associated with ALCL, among which the ATIC-ALK rearrangement resulting from the inv(2)(p23q35) translocation is probably the most recurrent [38].

Analytical, diagnostic and therapeutic context of ALK


  1. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Morris, S.W., Kirstein, M.N., Valentine, M.B., Dittmer, K.G., Shapiro, D.N., Saltman, D.L., Look, A.T. Science (1994) [Pubmed]
  2. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Hernández, L., Pinyol, M., Hernández, S., Beà, S., Pulford, K., Rosenwald, A., Lamant, L., Falini, B., Ott, G., Mason, D.Y., Delsol, G., Campo, E. Blood (1999) [Pubmed]
  3. Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Drexler, H.G., Gignac, S.M., von Wasielewski, R., Werner, M., Dirks, W.G. Leukemia (2000) [Pubmed]
  4. Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. Lamant, L., Gascoyne, R.D., Duplantier, M.M., Armstrong, F., Raghab, A., Chhanabhai, M., Rajcan-Separovic, E., Raghab, J., Delsol, G., Espinos, E. Genes Chromosomes Cancer (2003) [Pubmed]
  5. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration. Voena, C., Conte, C., Ambrogio, C., Boeri Erba, E., Boccalatte, F., Mohammed, S., Jensen, O.N., Palestro, G., Inghirami, G., Chiarle, R. Cancer Res. (2007) [Pubmed]
  6. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Takeuchi, K., Choi, Y.L., Togashi, Y., Soda, M., Hatano, S., Inamura, K., Takada, S., Ueno, T., Yamashita, Y., Satoh, Y., Okumura, S., Nakagawa, K., Ishikawa, Y., Mano, H. Clin. Cancer Res. (2009) [Pubmed]
  7. EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Sakairi, Y., Nakajima, T., Yasufuku, K., Ikebe, D., Kageyama, H., Soda, M., Takeuchi, K., Itami, M., Iizasa, T., Yoshino, I., Mano, H., Kimura, H. Clin. Cancer Res. (2010) [Pubmed]
  8. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Camidge, D.R., Kono, S.A., Flacco, A., Tan, A.C., Doebele, R.C., Zhou, Q., Crino, L., Franklin, W.A., Varella-Garcia, M. Clin. Cancer Res. (2010) [Pubmed]
  9. Activation of HER Family Signaling as a Mechanism of Acquired Resistance to ALK Inhibitors in EML4-ALK-Positive Non-Small Cell Lung Cancer. Tanizaki, J., Okamoto, I., Okabe, T., Sakai, K., Tanaka, K., Hayashi, H., Kaneda, H., Takezawa, K., Kuwata, K., Yamaguchi, H., Hatashita, E., Nishio, K., Nakagawa, K. Clin. Cancer Res. (2012) [Pubmed]
  10. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Morris, S.W., Kirstein, M.N., Valentine, M.B., Dittmer, K., Shapiro, D.N., Look, A.T., Saltman, D.L. Science (1995) [Pubmed]
  11. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Galkin, A.V., Melnick, J.S., Kim, S., Hood, T.L., Li, N., Li, L., Xia, G., Steensma, R., Chopiuk, G., Jiang, J., Wan, Y., Ding, P., Liu, Y., Sun, F., Schultz, P.G., Gray, N.S., Warmuth, M. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  12. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Kasprzycka, M., Marzec, M., Liu, X., Zhang, Q., Wasik, M.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Proteomic identification of oncogenic chromosomal translocation partners encoding chimeric anaplastic lymphoma kinase fusion proteins. Elenitoba-Johnson, K.S., Crockett, D.K., Schumacher, J.A., Jenson, S.D., Coffin, C.M., Rockwood, A.L., Lim, M.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  14. Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Touriol, C., Greenland, C., Lamant, L., Pulford, K., Bernard, F., Rousset, T., Mason, D.Y., Delsol, G. Blood (2000) [Pubmed]
  15. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. Shi, X., Franko, B., Frantz, C., Amin, H.M., Lai, R. Br. J. Haematol. (2006) [Pubmed]
  16. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form. ten Berge, R.L., Snijdewint, F.G., von Mensdorff-Pouilly, S., Poort-Keesom, R.J., Oudejans, J.J., Meijer, J.W., Willemze, R., Hilgers, J., Meijer, C.J. J. Clin. Pathol. (2001) [Pubmed]
  17. Low frequency association of the t(2;5)(p23;q35) chromosomal translocation with CD30+ lymphomas from American and Asian patients. A reverse transcriptase-polymerase chain reaction study. Lopategui, J.R., Sun, L.H., Chan, J.K., Gaffey, M.J., Frierson, H.F., Glackin, C., Weiss, L.M. Am. J. Pathol. (1995) [Pubmed]
  18. Immunohistochemical screening for oncogenic tyrosine kinase activation. Pulford, K., Delsol, G., Roncador, G., Biddolph, S., Jones, M., Mason, D.Y. J. Pathol. (1999) [Pubmed]
  19. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Bai, R.Y., Ouyang, T., Miething, C., Morris, S.W., Peschel, C., Duyster, J. Blood (2000) [Pubmed]
  20. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Gascoyne, R.D., Lamant, L., Martin-Subero, J.I., Lestou, V.S., Harris, N.L., Müller-Hermelink, H.K., Seymour, J.F., Campbell, L.J., Horsman, D.E., Auvigne, I., Espinos, E., Siebert, R., Delsol, G. Blood (2003) [Pubmed]
  21. Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo. Coluccia, A.M., Perego, S., Cleris, L., Gunby, R.H., Passoni, L., Marchesi, E., Formelli, F., Gambacorti-Passerini, C. Blood (2004) [Pubmed]
  22. Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. Cussac, D., Greenland, C., Roche, S., Bai, R.Y., Duyster, J., Morris, S.W., Delsol, G., Allouche, M., Payrastre, B. Blood (2004) [Pubmed]
  23. Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Bonvini, P., Gastaldi, T., Falini, B., Rosolen, A. Cancer Res. (2002) [Pubmed]
  24. Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Vega, F., Medeiros, L.J., Leventaki, V., Atwell, C., Cho-Vega, J.H., Tian, L., Claret, F.X., Rassidakis, G.Z. Cancer Res. (2006) [Pubmed]
  25. The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas. Raetz, E.A., Perkins, S.L., Carlson, M.A., Schooler, K.P., Carroll, W.L., Virshup, D.M. Am. J. Pathol. (2002) [Pubmed]
  26. Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase. Tartari, C.J., Gunby, R.H., Coluccia, A.M., Sottocornola, R., Cimbro, B., Scapozza, L., Donella-Deana, A., Pinna, L.A., Gambacorti-Passerini, C. J. Biol. Chem. (2008) [Pubmed]
  27. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Doebele, R.C., Pilling, A.B., Aisner, D.L., Kutateladze, T.G., Le, A.T., Weickhardt, A.J., Kondo, K.L., Linderman, D.J., Heasley, L.E., Franklin, W.A., Varella-Garcia, M., Camidge, D.R. Clin. Cancer Res. (2012) [Pubmed]
  28. Variants on a theme: a biomarker of crizotinib response in ALK-positive non-small cell lung cancer? Crystal, A.S., Shaw, A.T. Clin. Cancer Res. (2012) [Pubmed]
  29. Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Bischof, D., Pulford, K., Mason, D.Y., Morris, S.W. Mol. Cell. Biol. (1997) [Pubmed]
  30. Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation. Perez-Pinera, P., Zhang, W., Chang, Y., Vega, J.A., Deuel, T.F. J. Biol. Chem. (2007) [Pubmed]
  31. Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Lai, R., Rassidakis, G.Z., Medeiros, L.J., Ramdas, L., Goy, A.H., Cutler, C., Fujio, Y., Kunisada, K., Amin, H.M., Gilles, F. Am. J. Pathol. (2004) [Pubmed]
  32. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Zamo, A., Chiarle, R., Piva, R., Howes, J., Fan, Y., Chilosi, M., Levy, D.E., Inghirami, G. Oncogene (2002) [Pubmed]
  33. Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Amin, H.M., Medeiros, L.J., Ma, Y., Feretzaki, M., Das, P., Leventaki, V., Rassidakis, G.Z., O'Connor, S.L., McDonnell, T.J., Lai, R. Oncogene (2003) [Pubmed]
  34. Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma. Cho-Vega, J.H., Rassidakis, G.Z., Amin, H.M., Tsioli, P., Spurgers, K., Remache, Y.K., Vega, F., Goy, A.H., Gilles, F., Medeiros, L.J. Leukemia (2004) [Pubmed]
  35. A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Lamant, L., Dastugue, N., Pulford, K., Delsol, G., Mariamé, B. Blood (1999) [Pubmed]
  36. NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma. Galietta, A., Gunby, R.H., Redaelli, S., Stano, P., Carniti, C., Bachi, A., Tucker, P.W., Tartari, C.J., Huang, C.J., Colombo, E., Pulford, K., Puttini, M., Piazza, R.G., Ruchatz, H., Villa, A., Donella-Deana, A., Marin, O., Perrotti, D., Gambacorti-Passerini, C. Blood (2007) [Pubmed]
  37. The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling. Staber, P.B., Vesely, P., Haq, N., Ott, R.G., Funato, K., Bambach, I., Fuchs, C., Schauer, S., Linkesch, W., Hrzenjak, A., Dirks, W.G., Sexl, V., Bergler, H., Kadin, M.E., Sternberg, D.W., Kenner, L., Hoefler, G. Blood (2007) [Pubmed]
  38. The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. Maes, B., Vanhentenrijk, V., Wlodarska, I., Cools, J., Peeters, B., Marynen, P., de Wolf-Peeters, C. Am. J. Pathol. (2001) [Pubmed]
  39. Activation of alpha-diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase. Bacchiocchi, R., Baldanzi, G., Carbonari, D., Capomagi, C., Colombo, E., van Blitterswijk, W.J., Graziani, A., Fazioli, F. Blood (2005) [Pubmed]
  40. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Iwahara, T., Fujimoto, J., Wen, D., Cupples, R., Bucay, N., Arakawa, T., Mori, S., Ratzkin, B., Yamamoto, T. Oncogene (1997) [Pubmed]
WikiGenes - Universities