Reactome | Ligand-independent dimerization of point mutants of ALK

Ligand-independent dimerization of point mutants of ALK

Stable Identifier

R-HSA-9700184

Type

Reaction [transition]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Ligand-independent dimerization of point mutants of ALK

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

In addition to 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 Janoueix-Lerosey, I, Lequin, D, Brugières, L, Ribeiro, A, de Pontual, L, Combaret, V, Raynal, V, Puisieux, A, Schleiermacher, G, Pierron, G, Valteau-Couanet, D, Frebourg, T, Michon, J, Lyonnet, S, Amiel, J, Delattre, O	Nature	2008
21596819	Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene Murugan, AK, Xing, M	Cancer Res.	2011
21838707	Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684 Schönherr, C, Ruuth, K, Yamazaki, Y, Eriksson, T, Christensen, J, Palmer, RH, Hallberg, B	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 Hallberg, B, Palmer, RH	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 Ceccon, M, Mologni, L, Giudici, G, Piazza, R, Pirola, A, Fontana, D, Gambacorti-Passerini, C	Mol. Cancer Res.	2015
18724359	Identification of ALK as a major familial neuroblastoma predisposition gene Mossé, YP, Laudenslager, M, Longo, L, Cole, KA, Wood, A, Attiyeh, EF, Laquaglia, MJ, Sennett, R, Lynch, JE, Perri, P, Laureys, G, Speleman, F, Kim, C, Hou, C, Hakonarson, H, Torkamani, A, Schork, NJ, Brodeur, GM, Tonini, GP, Rappaport, E, Devoto, M, Maris, JM	Nature	2008
23104988	Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma Chand, D, Yamazaki, Y, Ruuth, K, Schönherr, C, Martinsson, T, Kogner, P, Attiyeh, EF, Maris, J, Morozova, O, Marra, MA, Ohira, M, Nakagawara, A, Sandström, PE, Palmer, RH, Hallberg, B	Dis Model Mech	2013
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
18923525	Activating mutations in ALK provide a therapeutic target in neuroblastoma George, RE, Sanda, T, Hanna, M, Fröhling, S, Luther, W, Zhang, J, Ahn, Y, Zhou, W, London, WB, McGrady, P, Xue, L, Zozulya, S, Gregor, VE, Webb, TR, Gray, NS, Gilliland, DG, Diller, L, Greulich, H, Morris, SW, Meyerson, M, Look, AT	Nature	2008
23239810	Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors Ceccon, M, Mologni, L, Bisson, W, Scapozza, L, 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 Wang, YW, Tu, PH, Lin, KT, Lin, SC, Ko, JY, Jou, YS	Neoplasia	2011
18923524	Oncogenic mutations of ALK kinase in neuroblastoma Chen, Y, Takita, J, Choi, YL, Kato, M, Ohira, M, Sanada, M, Wang, L, Soda, M, Kikuchi, A, Igarashi, T, Nakagawara, A, Hayashi, Y, Mano, H, Ogawa, S	Nature	2008