Ligand-independent dimerization of point mutants of ALK

Stable Identifier
Reaction [transition]
Homo sapiens
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In addition activation by translocations that lead to the formation of ALK fusion proteins, the ALK locus is also subject to activating point mutations (reviewed in Roskoski, 2013; Hallberg and Palmer, 2016; Della Corte et al, 2018). ALK mutations are most prevalent in neuroblastoma, where they are present in 7% of sporadic and up to 50% of familial cases, but also occur at lower frequencies in non-small cell lung cancer, anaplastic thyroid cancer among other cancers (Mosse et al, 2008; Chand et al, 2013; Schonherr et al, 2011; George et al, 2008; Janoueix-Lerousy et al, 2008; reviewed in Della Corte et al, 2018). Missense mutations tend to cluster in the kinase domain, but are also found in the juxtamembrane and extracellular regions (Chen et al, 2008; Murugan et al, 2011; Wang et al, 2011). Activating mutations have been shown in several cases to lead to ligand-independent dimerization and activation, and to promote oncogenic transformation in vitro and in vivo, while some ALK mutations identified in cancers retain dependence on ligand binding (Chand et al, 2008; Schonherr et al, 2011; Chen et al, 2008; George et al, 2008; Mosse et al, 2008; Ceccon et al, 2013; Ceccon et al, 2015; Murugan et al, 2011; Wang et al, 2011; reviewed in Della Corte et al, 2018).

Literature References
PubMed ID Title Journal Year
18923523 Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Schleiermacher, G, Lequin, D, Pierron, G, de Pontual, L, Michon, J, Valteau-Couanet, D, Amiel, J, Raynal, V, Delattre, O, Puisieux, A, Lyonnet, S, Ribeiro, A, Frebourg, T, Combaret, V, Janoueix-Lerosey, I, Brugières, L

Nature 2008
21596819 Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene

Xing, M, Murugan, AK

Cancer Res. 2011
21838707 Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684

Schönherr, C, Eriksson, T, Christensen, J, Palmer, RH, Hallberg, B, Ruuth, K, Yamazaki, Y

Biochem J 2011
27573755 The role of the ALK receptor in cancer biology

Hallberg, B, Palmer, RH

Ann Oncol 2016
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
25421750 Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma

Piazza, R, Ceccon, M, Giudici, G, Mologni, L, Fontana, D, Gambacorti-Passerini, C, Pirola, A

Mol. Cancer Res. 2015
18724359 Identification of ALK as a major familial neuroblastoma predisposition gene

Hakonarson, H, Kim, C, Speleman, F, Laureys, G, Mossé, YP, Hou, C, Schork, NJ, Maris, JM, Tonini, GP, Devoto, M, Attiyeh, EF, Rappaport, E, Laudenslager, M, Cole, KA, Wood, A, Lynch, JE, Sennett, R, Laquaglia, MJ, Longo, L, Torkamani, A, Perri, P, Brodeur, GM

Nature 2008
23104988 Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma

Ohira, M, Marra, MA, Palmer, RH, Nakagawara, A, Attiyeh, EF, Schönherr, C, Kogner, P, Sandström, PE, Morozova, O, Martinsson, T, Maris, J, Hallberg, B, Ruuth, K, Yamazaki, Y, Chand, D

Dis Model Mech 2013
29455642 Role and targeting of anaplastic lymphoma kinase in cancer

Troiani, T, Viscardi, G, Morgillo, F, Fasano, M, Martinelli, E, Ciardiello, F, Della Corte, CM, Di Liello, R

Mol. Cancer 2018
18923525 Activating mutations in ALK provide a therapeutic target in neuroblastoma

Zozulya, S, George, RE, Gilliland, DG, Morris, SW, Luther, W, London, WB, Hanna, M, Meyerson, M, McGrady, P, Sanda, T, Gregor, VE, Look, AT, Zhang, J, Fröhling, S, Ahn, Y, Diller, L, Webb, TR, Zhou, W, Greulich, H, Gray, NS, Xue, L

Nature 2008
23239810 Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors

Ceccon, M, Mologni, L, Scapozza, L, Bisson, W, Gambacorti-Passerini, C

Mol. Cancer Res. 2013
23201355 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Roskoski, R

Pharmacol. Res. 2013
21847362 Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer

Lin, SC, Tu, PH, Wang, YW, Lin, KT, Jou, YS, Ko, JY

Neoplasia 2011
18923524 Oncogenic mutations of ALK kinase in neuroblastoma

Ohira, M, Kikuchi, A, Soda, M, Kato, M, Choi, YL, Nakagawara, A, Hayashi, Y, Wang, L, Ogawa, S, Chen, Y, Sanada, M, Takita, J, Mano, H, Igarashi, T

Nature 2008
Normal reaction
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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