Reactome | Ligand-independent dimerization of ALK fusions

Ligand-independent dimerization of ALK fusions

Stable Identifier

R-HSA-9700179

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Ligand-independent dimerization of ALK fusions

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The ALK locus is subject to chromosomal translocations and inversions that give rise to oncogenic fusion proteins in a number of different cancers. To date, ALK has been identified as a fusion partner with more than 25 proteins in cancers ranging from anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), diffuse B-cell lymphoma, neuroblastoma, rhabdomyosarcoma and inflammatory myofibroblastic tumors, among others (reviewed in Roskoski, 2013; Della Corte et al, 2018). These fusion proteins form constitutive, ligand-independent dimers by virtue of an N-terminal dimerization domain contributed by the fusion partner, and retain the intracellular region of the ALK receptor tyrosine kinase. Expression (and often overexpression) of the fusion proteins is regulated by the promoter of the fusion partner. Signaling downstream of the fusion proteins occurs through numerous pathways including the MAP kinase, PI3K and STAT cascades, among others, but the extent to which each pathway is activated downstream of the different fusions varies (Armstrong et al, 2004; reviewed in Hallberg and Palmer, 2013; Hallberg and Palmer, 2016; Della Corte et al, 2018, Roskoski, 2013).
The best characterized ALK fusion protein is NPM-ALK, which occurs in 75-80% of ALCLs, and fuses the intracellular portion of ALK with the N-terminal region of nucleophosmin, a protein involved in DNA repair, transcription and genome stability. NPM-ALK constitutively dimerizes based on the N-terminal NPM region. Deletion of the N-terminal domain abrogates oligomerization and abolishes the transformation activity of the protein (Morris et al, 1995; Fujimoto et al, 1996).
In addition to NPM, fusions with ALK have also been identified with EML4 (Soda et al, 2007; Choi et al, 2008; Takezawa et al, 2011), CLTC (De Paepe et al, 2003; Cherchetti et al, 2011; Chiakatsu et al, 2003), TPM3 (Lamant et al, 1999; Lawrence et al, 2000), TPM4 (Lawrence et al, 2000), RANBP2 (Marino-Enriquez et al, 2011a; Lee et al, 2017; Chen et al, 2008), STRN (Majewska et al, 2013; Perot et al, 2014; Kelly et al, 2014), ATIC (Colleoni et al, 2000; Trinei et al, 2000; Ma et al, 2000), KIF5B (Wong et al, 2011), TFG (Hernandez et al, 1999; Hernandez et al, 2002), HIP1 (Ou et al, 2014; Hong et al, 2014; Fang et al, 2014), CARS1 (Cools et al, 2002; Debelenko et al, 2003), PPF1BP1 (Takeuchi et al, 2011; Yoshida et al, 2013), MSN (Tort et al, 2001), VCL (Marino-Enriquez et al, 2011b; Debelenko et al, 2011), KLC1 (Togayashi et al, 2012), SEC31A (Panagopoulos et al, 2006), SQSTM1 (Iyevleva et al, 2015; Takeuchi et al, 2011), TPR (Choi et al, 2014), WDCP (Lipson et al, 2012), RRBP1 (Lee et al, 2017), DCTN1 (Subbiah et al, 2015; Lee et al, 2017; Iyevleva et al, 2015; Wang et al, 2012; Wiesner et al, 2014), EEF1A (van der Krogt et al, 2017), BIRC6 (Shan et al, 2015), EIF2AK3 (Ali et al, 2016), PPM1B (Ali et al, 2016), PRKAR1A (Ali et al, 2016), GCC2 (Noh et al, 2017), BCL11A (Tian et al, 2007) and LMO7 (Noh et al, 2017).

Literature References

PubMed ID	Title	Journal	Year
22347464	KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only Togashi, Y, Soda, M, Sakata, S, Sugawara, E, Hatano, S, Asaka, R, Nakajima, T, Mano, H, Takeuchi, K	PLoS One	2012
28659337	Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene van der Krogt, JA, Bempt, MV, Ferreiro, JF, Mentens, N, Jacobs, K, Pluys, U, Doms, K, Geerdens, E, Uyttebroeck, A, Pierre, P, Michaux, L, Devos, T, Vandenberghe, P, Tousseyn, T, Cools, J, Wlodarska, I	Haematologica	2017
24613930	Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer Kelly, LM, Barila, G, Liu, P, Evdokimova, VN, Trivedi, S, Panebianco, F, Gandhi, M, Carty, SE, Hodak, SP, Luo, J, Dacic, S, Yu, YP, Nikiforova, MN, Ferris, RL, Altschuler, DL, Nikiforov, YE	Proc Natl Acad Sci U S A	2014
27573755	The role of the ALK receptor in cancer biology Hallberg, B, Palmer, RH	Ann Oncol	2016
28741662	Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer Noh, KW, Lee, MS, Lee, SE, Song, JY, Shin, HT, Kim, YJ, Oh, DY, Jung, K, Sung, M, Kim, M, An, S, Han, J, Shim, YM, Zo, JI, Kim, J, Park, WY, Lee, SH, Choi, YL	J Pathol	2017
12920229	ALK+, CD30-, CD20- large B-cell lymphoma containing anaplastic lymphoma kinase (ALK) fused to clathrin heavy chain gene (CLTC) Chikatsu, N, Kojima, H, Suzukawa, K, Shinagawa, A, Nagasawa, T, Ozawa, H, Yamashita, Y, Mori, N	Mod Pathol	2003
10702393	ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35) Colleoni, GW, Bridge, JA, Garicochea, B, Liu, J, Filippa, DA, Ladanyi, M	Am J Pathol	2000
21164297	Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK Mariño-Enríquez, A, Wang, WL, Roy, A, Lopez-Terrada, D, Lazar, AJ, Fletcher, CD, Coffin, CM, Hornick, JL	Am. J. Surg. Pathol.	2011
26062823	STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion Subbiah, V, McMahon, C, Patel, S, Zinner, R, Silva, EG, Elvin, JA, Subbiah, IM, Ohaji, C, Ganeshan, DM, Anand, D, Levenback, CF, Berry, J, Brennan, T, Chmielecki, J, Chalmers, ZR, Mayfield, J, Miller, VA, Stephens, PJ, Ross, JS, Ali, SM	J Hematol Oncol	2015
11943732	Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity Hernández, L, Beà, S, Bellosillo, B, Pinyol, M, Falini, B, Carbone, A, Ott, G, Rosenwald, A, Fernández, A, Pulford, K, Mason, D, Morris, SW, Santos, E, Campo, E	Am. J. Pathol.	2002
24445538	Kinase fusions are frequent in Spitz tumours and spitzoid melanomas Wiesner, T, He, J, Yelensky, R, Esteve-Puig, R, Botton, T, Yeh, I, Lipson, D, Otto, G, Brennan, K, Murali, R, Garrido, M, Miller, VA, Ross, JS, Berger, MF, Sparatta, A, Palmedo, G, Cerroni, L, Busam, KJ, Kutzner, H, Cronin, MT, Stephens, PJ, Bastian, BC	Nat Commun	2014
10934142	TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors Lawrence, B, Perez-Atayde, A, Hibbard, MK, Rubin, BP, Dal Cin, P, Pinkus, JL, Pinkus, GS, Xiao, S, Yi, ES, Fletcher, CD, Fletcher, JA	Am J Pathol	2000
25813404	Novel ALK fusion partners in lung cancer Iyevleva, AG, Raskin, GA, Tiurin, VI, Sokolenko, AP, Mitiushkina, NV, Aleksakhina, SN, Garifullina, AR, Strelkova, TN, Merkulov, VO, Ivantsov, AO, Kuligina, ESh, Pozharisski, KM, Togo, AV, Imyanitov, EN	Cancer Lett	2015
12750159	ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma De Paepe, P, Baens, M, van Krieken, H, Verhasselt, B, Stul, M, Simons, A, Poppe, B, Laureys, G, Brons, P, Vandenberghe, P, Speleman, F, Praet, M, De Wolf-Peeters, C, Marynen, P, Wlodarska, I	Blood	2003
21134980	Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma Takeuchi, K, Soda, M, Togashi, Y, Ota, Y, Sekiguchi, Y, Hatano, S, Asaka, R, Noguchi, M, Mano, H	Haematologica	2011
27874193	ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma Lee, JC, Li, CF, Huang, HY, Zhu, MJ, Mariño-Enríquez, A, Lee, CT, Ou, WB, Hornick, JL, Fletcher, JA	J. Pathol.	2017
27245569	Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization Ali, SM, Hensing, T, Schrock, AB, Allen, J, Sanford, E, Gowen, K, Kulkarni, A, He, J, Suh, JH, Lipson, D, Elvin, JA, Yelensky, R, Chalmers, Z, Chmielecki, J, Peled, N, Klempner, SJ, Firozvi, K, Frampton, GM, Molina, JR, Menon, S, Brahmer, JR, MacMahon, H, Nowak, J, Ou, SH, Zauderer, M, Ladanyi, M, Zakowski, M, Fischbach, N, Ross, JS, Stephens, PJ, Miller, VA, Wakelee, H, Ganesan, S, Salgia, R	Oncologist	2016
21415216	Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer Takezawa, K, Okamoto, I, Nishio, K, Jänne, PA, Nakagawa, K	Clin. Cancer Res.	2011
8633037	Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5) Fujimoto, J, Shiota, M, Iwahara, T, Seki, N, Satoh, H, Mori, S, Yamamoto, T	Proc. Natl. Acad. Sci. U.S.A.	1996
17625570	Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Soda, M, Choi, YL, Enomoto, M, Takada, S, Yamashita, Y, Ishikawa, S, Fujiwara, S, Watanabe, H, Kurashina, K, Hatanaka, H, Bando, M, Ohno, S, Ishikawa, Y, Aburatani, H, Niki, T, Sohara, Y, Sugiyama, Y, Mano, H	Nature	2007
22327622	Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies Lipson, D, Capelletti, M, Yelensky, R, Otto, G, Parker, A, Jarosz, M, Curran, JA, Balasubramanian, S, Bloom, T, Brennan, KW, Donahue, A, Downing, SR, Frampton, GM, Garcia, L, Juhn, F, Mitchell, KC, White, E, White, J, Zwirko, Z, Peretz, T, Nechushtan, H, Soussan-Gutman, L, Kim, J, Sasaki, H, Kim, HR, Park, SI, Ercan, D, Sheehan, CE, Ross, JS, Cronin, MT, Jänne, PA, Stephens, PJ	Nat. Med.	2012
28404650	Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient Tian, Q, Deng, WJ, Li, ZW	Eur Respir J	2017
24475247	Identification of a recurrent STRN/ALK fusion in thyroid carcinomas Pérot, G, Soubeyran, I, Ribeiro, A, Bonhomme, B, Savagner, F, Boutet-Bouzamondo, N, Hostein, I, Bonichon, F, Godbert, Y, Chibon, F	PLoS One	2014
10556217	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, DY, Delsol, G, Campo, E	Blood	1999
18701132	An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features Chen, ST, Lee, JC	Hum. Pathol.	2008
23661334	Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing Majewski, IJ, Mittempergher, L, Davidson, NM, Bosma, A, Willems, SM, Horlings, HM, de Rink, I, Greger, L, Hooijer, GK, Peters, D, Nederlof, PM, Hofland, I, de Jong, J, Wesseling, J, Kluin, RJ, Brugman, W, Kerkhoven, R, Nieboer, F, Roepman, P, Broeks, A, Muley, TR, Jassem, J, Niklinski, J, van Zandwijk, N, Brazma, A, Oshlack, A, van den Heuvel, M, Bernards, R	J. Pathol.	2013
24736082	A novel fusion of TPR and ALK in lung adenocarcinoma Choi, YL, Lira, ME, Hong, M, Kim, RN, Choi, SJ, Song, JY, Pandy, K, Mann, DL, Stahl, JA, Peckham, HE, Zheng, Z, Han, J, Mao, M, Kim, J	J Thorac Oncol	2014
23201355	Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition Roskoski, R	Pharmacol. Res.	2013
21213368	ALK rearrangement in sickle cell trait-associated renal medullary carcinoma Mariño-Enríquez, A, Ou, WB, Weldon, CB, Fletcher, JA, Pérez-Atayde, AR	Genes Chromosomes Cancer	2011
15208656	Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells Armstrong, F, Duplantier, MM, Trempat, P, Hieblot, C, Lamant, L, Espinos, E, Racaud-Sultan, C, Allouche, M, Campo, E, Delsol, G, Touriol, C	Oncogene	2004
24518094	HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma Hong, M, Kim, RN, Song, JY, Choi, SJ, Oh, E, Lira, ME, Mao, M, Takeuchi, K, Han, J, Kim, J, Choi, YL	J Thorac Oncol	2014
23957430	Inflammatory myofibroblastic tumour of the lung with a novel PPFIBP1-ALK fusion variant Yoshida, A, Shibata, T, Tsuta, K, Watanabe, S, Tsuda, H	Histopathology	2013
26001147	BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib Shan, L, Jiang, P, Xu, F, Zhang, W, Guo, L, Wu, J, Zeng, Y, Jiao, Y, Ying, J	J Thorac Oncol	2015
21656749	A novel KIF5B-ALK variant in nonsmall cell lung cancer Wong, DW, Leung, EL, Wong, SK, Tin, VP, Sihoe, AD, Cheng, LC, Au, JS, Chung, LP, Wong, MP	Cancer	2011
18593892	Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer Choi, YL, Takeuchi, K, Soda, M, Inamura, K, Togashi, Y, Hatano, S, Enomoto, M, Hamada, T, Haruta, H, Watanabe, H, Kurashina, K, Hatanaka, H, Ueno, T, Takada, S, Yamashita, Y, Sugiyama, Y, Ishikawa, Y, Mano, H	Cancer Res.	2008
10216106	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
10706082	A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma Trinei, M, Lanfrancone, L, Campo, E, Pulford, K, Mason, DY, Pelicci, PG, Falini, B	Cancer Res	2000
29455642	Role and targeting of anaplastic lymphoma kinase in cancer Della Corte, CM, Viscardi, G, Di Liello, R, Fasano, M, Martinelli, E, Troiani, T, Ciardiello, F, Morgillo, F	Mol. Cancer	2018
10706887	Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis Ma, Z, Cools, J, Marynen, P, Cui, X, Siebert, R, Gesk, S, Schlegelberger, B, Peeters, B, De Wolf-Peeters, C, Wlodarska, I, Morris, SW	Blood	2000
25393796	Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib Ou, SH, Klempner, SJ, Greenbowe, JR, Azada, M, Schrock, AB, Ali, SM, Ross, JS, Stephens, PJ, Miller, VA	J Thorac Oncol	2014
12112524	Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor Cools, J, Wlodarska, I, Somers, R, Mentens, N, Pedeutour, F, Maes, B, De Wolf-Peeters, C, Pauwels, P, Hagemeijer, A, Marynen, P	Genes Chromosomes Cancer	2002
24060861	Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology Hallberg, B, Palmer, RH	Nat. Rev. Cancer	2013
22658521	Fusion of dynactin 1 to anaplastic lymphoma kinase in inflammatory myofibroblastic tumor Wang, X, Krishnan, C, Nguyen, EP, Meyer, KJ, Oliveira, JL, Yang, P, Yi, ES, Erickson-Johnson, MR, Yaszemski, MJ, Maran, A, Oliveira, AM	Hum Pathol	2012
24496003	HIP1-ALK, a novel ALK fusion variant that responds to crizotinib Fang, DD, Zhang, B, Gu, Q, Lira, M, Xu, Q, Sun, H, Qian, M, Sheng, W, Ozeck, M, Wang, Z, Zhang, C, Chen, X, Chen, KX, Li, J, Chen, SH, Christensen, J, Mao, M, Chan, CC	J Thorac Oncol	2014
7824924	Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma Morris, SW, Kirstein, MN, Valentine, MB, Dittmer, K, Shapiro, DN, Look, AT, Saltman, DL	Science	1995
16161041	Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor Panagopoulos, I, Nilsson, T, Domanski, HA, Isaksson, M, Lindblom, P, Mertens, F, Mandahl, N	Int J Cancer	2006
21494621	Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas Cerchietti, L, Damm-Welk, C, Vater, I, Klapper, W, Harder, L, Pott, C, Yang, SN, Reiter, A, Siebert, R, Melnick, A, Woessmann, W	PLoS One	2011
11310834	Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma Tort, F, Pinyol, M, Pulford, K, Roncador, G, Hernández, L, Nayach, I, Kluin-Nelemans, HC, Kluin, P, Touriol, C, Delsol, G, Mason, D, Campo, E	Lab Invest	2001