Tyrosine-phosphorylated SOCS3 negatively regulates cellular transformation mediated by the myeloproliferative neoplasm-associated JAK2 V617F mutant
Related Experiment Video
Updated: Jan 22, 2026
Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
Published on: September 6, 2024
Megumi Funakoshi-Tago1, Rina Tsuruya1, Fumihito Ueda1
1Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
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.
Insights
Suppressor of cytokine signaling 3 (SOCS3) inhibits Janus kinase 2 (JAK2) V617F mutant-driven cancer. SOCS3 suppresses tumor growth by downregulating JAK2 V617F expression and signaling.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- The Janus kinase 2 (JAK2) V617F mutation is prevalent in myeloproliferative neoplasms (MPNs).
- This mutation activates aberrant signaling pathways, contributing to oncogenesis.
- Understanding regulators of this pathway is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of suppressor of cytokine signaling 3 (SOCS3) in regulating the JAK2 V617F signaling pathway.
- To determine if SOCS3 exhibits tumor suppressive activity against JAK2 V617F-induced transformation.
- To elucidate the molecular mechanisms by which SOCS3 interacts with and inhibits JAK2 V617F.
Main Methods:
- Utilized Ba/F3 cell lines expressing JAK2 V617F and erythropoietin receptor (EpoR).
- Performed gene knockdown and enforced expression of SOCS3.
- Analyzed downstream signaling mediators (STAT3, STAT5, ERK) activation.
- Assessed cell proliferation and tumorigenesis.
- Investigated SOCS3-JAK2V617F interaction using mutant SOCS3 constructs.
Main Results:
- SOCS3 demonstrated tumor suppressive activity against JAK2 V617F-induced cellular transformation.
- SOCS3 knockdown enhanced JAK2 V617F expression, downstream signaling, proliferation, and tumorigenesis.
- Enforced SOCS3 expression inhibited JAK2 V617F signaling, proliferation, and tumorigenesis by downregulating JAK2 V617F.
- SOCS3 interacted with JAK2V617F via its SH2 domain and was phosphorylated at Tyr-204 and Tyr-221.
- Mutations in SOCS3's SH2 domain (R71E) or Tyr-221 (Y221F) abolished its inhibitory effects.
Conclusions:
- SOCS3 acts as a tumor suppressor in the context of JAK2 V617F-driven myeloproliferative neoplasms.
- SOCS3 inhibits oncogenic signaling by downregulating JAK2 V617F expression.
- The interaction of SOCS3 with JAK2V617F through its SH2 domain and phosphorylation at Tyr-221 are critical for its tumor suppressive function.
Related Concept Videos
01:23Negative Regulator Molecules
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
02:58Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:04Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
01:26Receptor Tyrosine Kinases
02:24Regulation of Expression Occurs at Multiple Steps
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...