ArticleCell death & disease2014
PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Cellular and clinical impact of protein phosphatase enzyme epigenetic silencing in multiple cancer tissues.Human genomics · 2024Article
- Advances of the multifaceted functions of PSTPIP2 in inflammatory diseases.Frontiers in immunology · 2024Review
- Proline-Serine-Threonine Phosphatase-Interacting Protein 2 Alleviates Diabetes Mellitus-Osteoarthritis in Rats through Attenuating Synovial Inflammation and Cartilage Injury.Orthopaedic surgery · 2021Article
- Role of the F-BAR Family Member PSTPIP2 in Autoinflammatory Diseases.Frontiers in immunology · 2021Review
- PSTPIP2 inhibits cisplatin-induced acute kidney injury by suppressing apoptosis of renal tubular epithelial cells.Cell death & disease · 2020Article
- Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis.Disease models & mechanisms · 2019Article
- Article
- PSTPIP2 Inhibits the Inflammatory Response and Proliferation of Fibroblast-Like SynoviocytesFrontiers in pharmacology · 2018Article
- Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation.British journal of pharmacology · 2017Article
- Novel function of FAXDC2 in megakaryopoiesis.Blood cancer journal · 2016Article
- Baicalein antagonizes acute megakaryoblastic leukemia in vitro and in vivo by inducing cell cycle arrest.Cell & bioscience · 2016Article
- Down syndrome and leukemia: insights into leukemogenesis and translational targets.Translational pediatrics · 2015Review
- miR-638 regulates differentiation and proliferation in leukemic cells by targeting cyclin-dependent kinase 2.The Journal of biological chemistry · 2015Article
- Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes.Journal of Zhejiang University. Science. BReview
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GATA1 mutations are tightly associated with transient myeloproliferative disorder (TMD) and acute megakaryoblstic leukemia (AMKL) in children with Down syndrome. Numerous genes are altered in GATA-1-deficient megakaryocytes, which may contribute to the hyperproliferation and abnormal terminal differentiation of these malignant cells. In this study, we demonstrate that Pstpip2 is a GATA-1-repressed gene that controls megakaryopoiesis. Ectopic expression of PSTPIP2 impaired megakaryocytic differentiation as evidenced by a decrease of CD41 expression and reduced DNA content in K562 cells. PSTPIP2 overexpression also caused enhanced activation of Src family kinases and subsequently reduced ERK phosphorylation. Consistently, PSTPIP2 knockdown showed the opposite effect on differentiation and signaling. Moreover, the W232A mutant of PSTPIP2, defective in its interaction with PEST family phosphatases that recruit c-Src terminal kinase (CSK) to suppress Src family kinases, failed to inhibit differentiation and lost its ability to enhance Src family kinases or reduce ERK phosphorylation. In fact, the W232A mutant of PSTPIP2 promoted megakaryocyte differentiation. These observations suggest that PSTPIP2 recruiting PEST phosphatases somehow blocked CSK activity and led to enhanced activation of Src family kinases and reduced ERK phosphorylation, which ultimately repressed megakaryocyte differentiation. Supporting this idea, PSTPIP2 interacted with LYN and the expression of a dominant negative LYN (LYN DN) overwhelmed the inhibitory effect of PSTPIP2 on differentiation and ERK signaling. In addition, a constitutively active LYN (LYN CA) normalized the enhanced megakaryocyte differentiation and repressed ERK signaling in PSTPIP2 knockdown cells. Finally, we found that PSTPIP2 repressed ERK signaling, differentiation, and proliferation and verified that PSTPIP2 upregulation repressed megakaryocyte development in primary mouse bone marrow cells. Our study thus reveals a novel mechanism by which dysregulation of PSTPIP2 due to GATA-1 deficiency may contribute to abnormal megakaryocyte proliferation and differentiation in pathogenesis of related diseases.
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