TYK2-dependent STAT1 and STAT3 phosphorylation

Stable Identifier
R-HSA-9851142
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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STAT1 and STAT3 are phosphorylated in ALK+ and ALK- ALCL in a manner that depends on active TYK2. Knockout or inhibition of TYK2 in ALCL human and mouse models abrogates STAT1 and STAT3 phosphorylation, decreases expression of MCL1 and increases cell death, implicating a TYK2-STAT-MCL signaling cascade in ALCL cell survival (Prutsch et al, 2019). Direct phosphorylation of STAT1 and STAT3 by TYK2 has not been demonstrated, nor has direct binding of either STAT to the promoter of the MCL1 gene, despite previous evidence supporting a JAK/STAT/MCL1 pathway (Prutsch et al, 2019; Rassidakis et al, 2002). Moreover, although autocrine stimulation of IL10 and IL22 has been implicated in the activation of TYK2 in these cells, the precise mechanism for TYK2 upregulation in ALCLs has not been determined (Prutsch et al, 2019).
STAT3 is a known effector of NPM1-ALK-mediated signaling, but the role of STAT1 is somewhat less clear (Crescenzo et al, 2015; Chiarle et al, 2005; reviewed in Chiarle, 2008). STAT1 has been described as a tumor suppressor in ALCL, and one study showed that STAT1 is downregulated in ALCL in an NPM1-ALK- and proteasome-dependent fashion (Wu et al, 2015; Avalle et al, 2012; Zhang and Liu, 2017).
Literature References
PubMed ID Title Journal Year
24058752 STAT1 and STAT3 in tumorigenesis: A matter of balance

Regis, G, Novelli, F, Poli, V, Pensa, S, Avalle, L

JAKSTAT 2012
25873174 Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma

Piva, R, Piris, MA, Inghirami, G, Cerroni, L, Rossi, D, Gaidano, G, Pileri, S, Paulli, M, Bertoni, F, Ponzoni, M, Vialard, JE, Todaro, M, Acquaviva, A, Tousseyn, T, Novero, D, Zamo', A, Mevellec, L, Gaudiano, M, Tiacci, E, Tzankov, A, Rosenwald, A, Lasorsa, E, Ciardullo, C, Boi, M, Di Giacomo, F, Ficarra, E, Chan, WC, Crescenzo, R, The European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium ‘‘Genetics-Driven Targeted Management of Lymphoid Malignancies, -, Falini, B, Weisenburger, D, Kenner, L, Iqbal, J, Rabadan, R, Chiesa, N, Spaccarotella, E, Abate, F, Tabbo', F, Ercole, E, Shultz, LD, Rinaldi, A, Barbarossa, L

Cancer Cell 2015
30131584 Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

Alvarez-Hernandez, A, Simonitsch-Klupp, I, Müller, M, Schlederer, M, Liang, HC, Wolf, P, Gurnhofer, E, Hielscher, T, Staber, PB, Sternberg, C, Svinka, J, Shirsath, N, Roos, S, Schmoellerl, J, Suske, T, Jäger, U, Leone, DA, Kornauth, C, Inghirami, GG, Eferl, R, Grebien, F, Prutsch, N, Aufinger, A, Moriggl, R, Strobl, B, Limberger, T, Stoiber, D, Wu, LC, Sanda, T, Look, AT, Turner, SD, Aberger, F, Kenner, L, Merkel, O

Leukemia 2019
25921060 STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma

Zhang, H, Bone, KM, Kneteman, NM, Gupta, N, Wu, F, Molavi, O, Gopal, K, Lewis, JT, Alshareef, A, Lai, R, Douglas, DN, Wu, C

Blood 2015
28950072 STAT1 in cancer: friend or foe?

Liu, Z, Zhang, Y

Discov Med 2017
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
12057933 Overexpression of Mcl-1 in anaplastic large cell lymphoma cell lines and tumors

Rassidakis, GZ, Sarris, AH, Cabanillas, F, Medeiros, LJ, Lai, R, McDonnell, TJ

Am J Pathol 2002
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Disease
Name Identifier Synonyms
anaplastic large cell lymphoma DOID:0050744
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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