ALK mutants bind STAT3

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Homo sapiens
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The STAT3 signaling pathway is a major downstream target of several oncogenic ALK proteins (Zamo et al, 2002; Zhang et al, 2002; Amin et al, 2003; Chiarle et al, 2003; Chiarle et al, 2005; Koivunen et al, 2008; Takezawa et al, 2011; Cerchietti et al, 2011; Wong et al, 2011; Okubo et al, 2012; Cazes et al, 2013; reviewed in Chiarle et al, 2008; Hallberg and Palmer 2013; Hallberg and Palmer, 2016). STAT3 is phosphorylated at tyrosine 705 downstream of active ALK and oncogenic ALK fusion proteins and contributes to cellular survival (Zamo et al, 2002; Zhang et al, 2002; Amin et al, 2003; Chiarle et al, 2003; Chiarle et al, 2005; reviewed in Chiarle et al, 2008; Palmer et al, 2009). Whether STAT3 activation downstream of ALK is mediated directly by the receptor itself or depends on JAK3 is controversial (Zhang et al, 2002; Han et al 2006 a,b; Lai et al, 2005; Marzec et al. 2005; Shi et al, 2006; reviewed in Palmer et al, 2009). STAT3 is also phosphorylated at serine 727 in a manner that depends on the PI3K, mTOR and MAPK pathways. The functional significance of S727 phsophorylation is not entirely clear (Gambi et al, 2019). STAT3 supports cell survival by promoting the expression of a number of cell cycle and anti-apoptotic genes (reviewed in Chiarle et al, 2008).

Literature References
PubMed ID Title Journal Year
27573755 The role of the ALK receptor in cancer biology

Hallberg, B, Palmer, RH

Ann Oncol 2016
11850821 Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death

Chiarle, R, Piva, R, Inghirami, G, Levy, DE, Howes, J, Fan, Y, Chilosi, M, Zamo, A

Oncogene 2002
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
18097461 The anaplastic lymphoma kinase in the pathogenesis of cancer

Chiarle, R, Piva, R, Ambrogio, C, Inghirami, G, Voena, C

Nat. Rev. Cancer 2008
15895073 Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Cai, H, Chiarle, R, Inghirami, G, Karras, JG, Levy, DE, Simmons, WJ, Zamo, A, Dhall, G, Raz, R

Nat. Med. 2005
16170336 Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

Wasik, MA, Wlodarski, P, Zhang, Q, Marzec, M, Odum, N, Kasprzycka, M, Ptasznik, A

Lab. Invest. 2005
16939498 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

Frantz, C, Amin, HM, Franko, B, Lai, R, Shi, X

Br. J. Haematol. 2006
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
30692217 The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3

Verma, A, Inghirami, G, Gambi, G, Wang, R, Elemento, O, Basso, V, Di Simone, E, Mondino, A, Ponzoni, M, Icardi, L, Ricci, L

Cancer Res. 2019
16153455 Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma

Amin, HM, Atwell, C, Rassidakis, GZ, Medeiros, LJ, Lin, Q, Lai, R

Hum. Pathol. 2005
21415216 Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer

Jänne, PA, Takezawa, K, Nishio, K, Nakagawa, K, Okamoto, I

Clin. Cancer Res. 2011
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
16825495 Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma

Frantz, C, Amin, HM, Franko, B, Han, Y, Lai, R, Shi, X

Blood 2006
16871283 Restoration of shp1 expression by 5-AZA-2'-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

Amin, HM, Franko, B, Frantz, C, Han, Y, Lai, R, Lin, Q, Lee, J

Leukemia 2006
11751994 Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma

Wasik, MA, Zhang, Q, Carpentieri, DF, Morris, S, Odum, N, Skorski, T, Raghunath, PN, Majewski, M, Xue, L

J. Immunol. 2002
12934099 Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma

Ma, Y, Amin, HM, Rassidakis, GZ, Feretzaki, M, Leventaki, V, Medeiros, LJ, Lai, R, McDonnell, TJ, O'Connor, SL, Das, P

Oncogene 2003
19459784 Anaplastic lymphoma kinase: signalling in development and disease

Grabbe, C, Vernersson, E, Palmer, RH, Hallberg, B

Biochem. J. 2009
12424201 NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors

Gong, JZ, Chiarle, R, Piva, R, Inghirami, G, Liu, J, Howes, J, Pesci, A, Simmons, WJ, Dhall, G, Cai, J, Guasparri, I

Blood 2003
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
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
Normal reaction
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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