ALK mutants bind PI3KR1

Stable Identifier
R-HSA-9712078
Type
Reaction [BlackBoxEvent]
Species
Homo sapiens
Compartment
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Various ALK fusions and point mutants have been shown to form stable, active complexes with the PI3K and to activate downstream signaling through AKT/PKB (Bai et al, 2000; Slupianek et al, 2001; Slupianek and Tomasz, 2004; Marzec et al, 2007; Chen et al, 2008; Chand et al, 2013; George et al, 2008; Janoieux-Lerousey et al, 2008; Wong et al, 2011; Cerchietti et al, 2011; Wiesner et al, 2014; Koivunen et al, 2008; Ren et al, 2012; Cazes et al, 2013; Okubo et al, 2103; reviewed in Della Corte et al, 2018; Hallberg and Palmer, 2013; Ducray et al, 2019). Attempts to define a binding site for the p85 regulatory subunit of PI3K on NPM-ALK identified fragment with a putative p85 phospho-tyrosine binding site that was capable of blocking the interaction of PIK3R1 when co-expressed. In spite of this, mutation of the putative tyrosine residue did not block PIK3R1 binding, suggesting that the interaction may be mediated by an adaptor protein. SHC, CRKL and GAB2 each formed complexes with both PIK3R1 and NPM-ALK as assessed by co-immunoprecipitation, making them candidates (Bai et al, 2000).
Signaling throught the PI3K/AKT pathway activates the anti-apoptotic pathway contributing to oncogenesis (Bai et al, 2000; Slupianek et al, 2001; reviewed in Rososki, 2013; Ducray et al, 2019).

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
21494621 Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas

Reiter, A, Siebert, R, Melnick, A, Pott, C, Damm-Welk, C, Yang, SN, Klapper, W, Harder, L, Vater, I, Woessmann, W, Cerchietti, L

PLoS One 2011
22249260 Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Hayashi, Y, Chen, Y, Igarashi, T, Hiwatari, M, Takita, J, Ogawa, S, Okubo, J, Nishimura, R, Sanada, M, Kato, M, Oki, K

Oncogene 2012
22570254 Identification of anaplastic lymphoma kinase as a potential therapeutic target in ovarian cancer

Haack, H, Ren, JM, Gu, TL, Zhu, X, Innocenti, G, Crosby, K, Tan, ZP, Moritz, A, Yang, YF, Ren, H, Rush, J, Beausoleil, S, Comb, MJ, Zhang, Y, Zhou, XM

Cancer Res 2012
17353907 Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway

Bucki, R, Raghunath, PN, El-Salem, M, Halasa, K, Liu, X, Wlodarski, P, Kasprzycka, M, Marzec, M, Wasik, MA

Oncogene 2007
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
18594010 EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

Koivunen, JP, Murphy, C, Thomas, R, Zejnullahu, K, Jänne, PA, Holmes, AJ, Ducko, C, Sugarbaker, DJ, Lifshits, E, Choi, HG, Chiang, D, Meyerson, M, Engelman, JA, Lee, C, Lindeman, N, Lee, J, Richards, WG, Marcoux, JP, Kim, J, Gray, NS, Mermel, C

Clin Cancer Res 2008
11110708 Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway

Ouyang, T, Morris, SW, Bai, RY, Duyster, J, Miething, C, Peschel, C

Blood 2000
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
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
24445538 Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

Palmedo, G, Botton, T, Yeh, I, Busam, KJ, Garrido, M, Cerroni, L, Bastian, BC, Murali, R, Wiesner, T, Kutzner, H, Ross, JS, Lipson, D, Cronin, MT, Berger, MF, He, J, Esteve-Puig, R, Stephens, PJ, Brennan, K, Miller, VA, Sparatta, A, Otto, G, Yelensky, R

Nat Commun 2014
31366041 The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Ducray, SP, Turner, SD, Garland, GD, Natarajan, K, Egger, G

Cancers (Basel) 2019
21656749 A novel KIF5B-ALK variant in nonsmall cell lung cancer

Leung, EL, Tin, VP, Wong, MP, Au, JS, Cheng, LC, Sihoe, AD, Wong, DW, Chung, LP, Wong, SK

Cancer 2011
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
11280786 Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis

Morrione, A, Xue, L, Hoser, G, Wasik, MA, Slupianek, A, Nieborowska-Skorska, M, Morris, SW, Majewski, M, Skorski, T

Cancer Res 2001
23201355 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Roskoski, R

Pharmacol. Res. 2013
23139213 Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma

Louis-Brennetot, C, Schleiermacher, G, Loew, D, Pierron, G, Ferrand, S, Daveau, R, Cappo, J, Vigny, M, Jouannet, S, Delattre, O, Dingli, F, Lombard, B, Boeva, V, Cazes, A, Janoueix-Lerosey, I, Combaret, V, Mazot, P, Barillot, E

Cancer Res 2013
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
15588951 NPM/ALK downregulates p27Kip1 in a PI-3K-dependent manner

Skorski, T, Slupianek, A

Exp. Hematol. 2004
Participants
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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