ArticleScientific reports2017
Cbl-mediated K63-linked ubiquitination of JAK2 enhances JAK2 phosphorylation and signal transduction.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Targeting DESI2 as a Novel Therapeutic Strategy for JAK2-Mutant Leukemias.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- miR-206 alleviates LPS-induced inflammatory injury in cardiomyocytes via directly targeting USP33 to inhibit the JAK2/STAT3 signaling pathway.Molecular and cellular biochemistry · 2024Article
- Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis.Journal of translational medicine · 2023Article
- ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2.Cell death and differentiation · 2023Article
- JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability.Cell death & disease · 2022Article
- Review
- Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3.Journal of translational medicine · 2021Article
- SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance.Cell death & disease · 2021Article
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- Review
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
JAK2 activation is crucial for cytokine receptor signal transduction and leukemogenesis. However, the underlying processes that lead to full activation of JAK2 are unclear. Here, we report a positive role for ubiquitination of JAK2 during GM-CSF-induced activation. Upon GM-CSF stimulation, JAK2 ubiquitination is significantly enhanced through K63-linked poly-ubiquitination. Studies employing both knockout and overexpression of Cbl, an E3 ubiquitin ligase, led to the conclusion that Cbl specifically promotes JAK2 ubiquitination, and this was further confirmed in vitro using a Cbl ubiquitination assay. Moreover, following GM-CSF stimulation, the levels of phospho-JAK2 and -STAT5 and a STAT5 luciferase reporter assay were all reduced in Cbl knockout cells and this effect could be rescued by Cbl expression. Mechanistically, Cbl can interact with, and ubiquitinate JAK2 FERM and kinase domains via the Cbl TKB domain. Using lysine-to-arginine site-directed mutagenesis, K970 in the kinase domain of JAK2 was identified as the ubiquitination site important for promoting full JAK2 activation by Cbl via K63-conjugated poly-ubiquitination. Our study suggests that GM-CSF-induced JAK2 activation is enhanced by Cbl-mediated ubiquitination of JAK2. Targeting ubiquitination of JAK2 might offer a novel therapeutic strategy against JAK2-mediated disorders.
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