Journal of Cell Science: Chinese Scientists Found a Protein Tyrosine Kinase Regulates ....
Journal of Cell Science: Chinese Scientists Found a Protein Tyrosine Kinase Regulates Erythroid Cell Development through STAT3 Dephosphorylation
April 24th, 2014, Beijing, China
“Protein Tyrosine Phosphatase PTPN9 Regulates Erythroid Cell Development through STAT3 Dephosphorylation in Zebrafish” is published online on Journal of Cell Science (April 11, 2014 doi: 10.1242/jcs.145367). This study is completed collaboratively by Prof. Jingwei Xiong lab from the Institute of Molecular Medicine, Peking University, and Dr. Kun Meng from Shenogen Pharma Group.
Protein tyrosine kinases and phosphatases (PTPs) play important role in cell proliferation, differentiation and migration through signal pathway regulation. Previous studies have shown that human PTPN9 functions in dephosphorylates different proteins for multiple functions, such as promoting homotypic vesicle fusion, mediating insulin signaling in hepatocytes, suppressing breast cancer cell growth, and regulating endothelial cell function. PTPN9 also directly interacts with STAT3 and mediates its dephosphorylation in breast cancer cells. STAT3 is a key factor in cell signaling, especially in tumor cells. It is reported that STAT3 acts as a biomarker of cancer treatment and prognosis due to its close relationship with cancer stem cell.
In this study, Prof. Xiong and Dr. Meng found that Ptpn9a, not Ptpn9b, played a crucial role in regulating erythroid cell development in zebrafish embryos. Depletion of PTPN9 in zebrafish embryos in vivo or K562 cells in vitro increased phosphorylated STAT3 (pSTAT3), and the hyper-phosphorylated STAT3 prevented GATA1 and ZBP-89 from regulating erythroid gene expression. These findings imply that PTPN9 plays an important role in erythropoiesis by disrupting an inhibitory complex of pSTAT3, GATA1 and ZBP-89, providing new cellular and molecular insights of ptpn9a into developmental hematopoiesis.
The first author is Dr. Ye Bu from the Institute of Molecular Medicine, Peking University. Prof. Xiong and Dr. Meng are co-corresponding authors.
Abstract:
Protein tyrosine phosphatases (PTPs) such as SHP-1, SHP-2 and CD45 are involved in hematopoiesis, but the function of many PTPs is not well characterized in vivo. Here we have identified Ptpn9a, an ortholog of human PTPN9, as a crucial regulator of erythroid cell development in zebrafish embryos. ptpn9a, but not ptpn9b, was expressed in the posterior lateral plate mesoderm and intermediate cell mass, two primitive hematopoietic sites during zebrafish embryogenesis. Morpholino-mediated knockdown of ptpn9a depleted erythrocytes by inhibiting erythroid cell maturation without affecting erythroid proliferation and apoptosis. Consistently, both dominant-negative PTPN9C515S and PTPN9 siRNA inhibited erythroid differentiation in human K562 cells. Mechanistically, depletion of PTPN9 in zebrafish embryos in vivo or K562 cells in vitro increased phosphorylated STAT3 (pSTAT3), and the hyper-phosphorylated STAT3 entrapped and prevented GATA1 and ZBP-89 from regulating erythroid gene expression. These findings imply that PTPN9 plays an important role in erythropoiesis by disrupting an inhibitory complex of pSTAT3, GATA1 and ZBP-89, providing new cellular and molecular insights of ptpn9a into developmental hematopoiesis.
Results:
ptpn9a is expressed in the primitive hematopoietic sites during zebrafish embryogenesis. Knockdown of ptpn9a diminishes the number of primitive erythrocytes. ptpn9a knockdown has no effect on erythroid cell proliferation and apoptosis in primitive hematopoiesis. PTPN9 is required for erythroid cell maturation. Increased STAT3 phosphorylation by knockdown of PTPN9 enhances formation of the STAT3-GATA1-ZBP-89 complex. Dephosphorylation of STAT3 by PTPN9 contributes to erythroid cell maturation.
About Shenogen
Shenogen Pharma Group is a drug discovery and development company based in Beijing, China, that dedicated the development of first-in-class therapeutics for cancer treatment. We possess robust intellectual property rights around a novel membrane-bound estrogen receptor, ER-alpha 36, which is related to tumor metastasis. Under the motto of “Better Medicine, Better Life” and a seasoned management team, together with our partners, Shenogen has developed an impressive product pipeline. Our pipeline consists of novel small molecule and antibody therapeutics for cancer treatment which includes liver cancer, breast cancer, other solid tumors and leukemia. Our lead molecule, icaritin, is currently in Ph II clinical trial for treatment of advanced hepatocellular carcinoma.