pY-STAT3 dimer translocates to the nucleus downstream of ALK mutants

Stable Identifier
R-HSA-9850958
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
cytosol, nucleoplasm
ReviewStatus
5/5
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pY-STAT3 dimer translocates to the nucleus downstream of ALK mutants
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STAT3 is a key regulator of transcriptional events downstream of oncogenic forms of ALK, including NPM-ALK (reviewed in Turner and Alexander, 2006; Chiarle et al, 2008; Ducray et al, 2019).
STAT3 is phosphorylated at tyrosine 705 downstream of active ALK and oncogenic ALK fusion proteins and contributes to cellular survival. Tyrosine phosphorylation at residue 705 is required for STAT3 dimerization, nuclear translocation, and DNA binding (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).
STAT3 is also phosphorylated at serine 727 in a manner that depends on the PI3K, mTOR and MAPK pathways. The functional significance of S727 phosphorylation is not entirely clear (Gambi et al, 2019).
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 supports cell survival by promoting the expression of a number of cell cycle and anti-apoptotic genes (reviewed in Chiarle et al, 2008; Ducray et al, 2019).
Literature References
PubMed ID Title Journal Year
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
18097461 The anaplastic lymphoma kinase in the pathogenesis of cancer

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

Nat. Rev. Cancer 2008
16482213 Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells

Turner, SD, Alexander, DR

Leukemia 2006
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
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
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
31366041 The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

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

Cancers (Basel) 2019
Participants
Input
Output
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as an event of
Disease
Name Identifier Synonyms
anaplastic large cell lymphoma DOID:0050744
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2023-10-14)
Reviewed
Turner, S  (2023-11-08)
Created
Rothfels, K  (2023-10-12)
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