Tyrosine-phosphorylated SOCS3 negatively regulates cellular transformation mediated by the myeloproliferative neoplasm-associated JAK2 V617F mutant. (November 2019)

• Record Type: Journal Article
• Authors: Funakoshi-Tago, Megumi; Tsuruya, Rina; Ueda, Fumihito; Ishihara, Aki; Kasahara, Tadashi; Tamura, Hiroomi; Tago, Kenji
• Is Part Of: Cytokine. Volume 123(2019)
• Publication Date: 2019-11
• Subjects: JAK2 V617F mutant -- Myeloproliferative neoplasms (MPNs) -- SOCS3 -- SH2 domain -- Phosphorylation; CHX cycloheximide -- CIS cytokine-inducible SH2-containing protein -- CML chronic myeloid leukemia -- EpoR erythropoietin receptor -- ERK extracellular signal-regulated kinase -- ET essential thrombocythemia -- FBS fetal bovine serum -- GFP green fluorescent protein -- HCC hepatocellular carcinoma -- ires internal ribosomal entry site -- JAK2 janus kinase 2 -- MPNs myeloproliferative neoplasms -- MSCV murine stem cell virus -- PI3K phosphoinositide 3-kinase -- PMF primary myelofibrosis -- PV polycythemia vera -- s.c. subcutaneous -- SH2 Src homology 2 -- SOCS suppressor of cytokine signaling proteins -- STAT signaling mediators including signal transducer and activator of transcription -- TpoR thrombopoietin receptor; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2019.154753
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: SOCS3 induces the degradation of the JAK2 V617F mutant. SOCS3 inhibits tumorigenesis induced by the JAK2 V617F mutant. The phosphorylation of SOCS3 may be essential for its inhibitory effects. Abstract: In the majority of myeloproliferative neoplasms (MPNs) patients, a point mutation, V617F has been found in Janus kinase 2 (JAK2) gene, and this JAK2 mutant provoked aberrant signaling pathway. In the current study, we found that suppressor of cytokine signaling proteins 3 (SOCS3) possessed the tumor suppressive activity against the JAK2 V617F mutant-provoked cellular transformation. The knockdown of SOCS3 increased the expression level of the JAK2 V617F mutant, which enhanced the activation of signaling mediators, including signal transducer and activator of transcription 3 and 5 (STAT3, STAT5) and extracellular signal-regulated kinase (ERK), and also increased of the proliferation rate and tumorigenesis activity of Ba/F3 cells expressing the JAK2 V617F mutant and erythropoietin receptor (EpoR). In contrast, the enforced expression of SOCS3 significantly inhibited the JAK2 V617F mutant-induced activation of downstream signaling molecules, cell proliferation, and tumorigenesis by down-regulating the expression level of the JAK2 V617F mutant. SOCS3 interacted with the JAK2V617F mutant through its SH2 domain and was phosphorylated at Tyr-204 and Tyr-221 in its SOCS box by the JAK2V617F mutant. SOCS3 mutants carrying a mutation in the SH2 domain (R71E) and a substitution at Tyr-221 (Y221F) failed to exert inhibitory effects on JAK2V617F mutant-induced cellular transformation and tumorigenesis. Collectively, these results imply that SOCS3 plays a negative role in the JAK2 V617F mutant-induced oncogenic signaling pathway through its SH2 domain and the phosphorylation of Tyr-221 in its SOCS box.