Browsing by Subject "Phosphoric monoester hydrolases"

Now showing 1 - 4 of 4
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    CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation
    (Elsevier, 2016-02-16) Kumar, Vinit; Cheng, Pingyan; Condamine, Thomas; Mony, Sridevi; Languino, Lucia R.; McCaffrey, Judith C.; Hockstein, Neil; Guarino, Michael; Masters, Gregory; Penman, Emily; Denstman, Fred; Xu, Xiaowei; Altieri, Dario C.; Du, Hong; Yan, Cong; Gabrilovich, Dmitry I.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.
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    OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome
    (Oxford University Press, 2012) Luo, Na; West, Callah C.; Murga-Zamalloa, Carlos A.; Sun, Lou; Anderson, Ryan M.; Wells, Clark D.; Weinreb, Robert N.; Travers, Jeffrey B.; Khanna, Hemant; Sun, Yang; Ophthalmology, School of Medicine
    Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.
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    PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371
    (American Society of Hematology, 2023) Chen, Hongxia; Bai, Yunpeng; Kobayashi, Michihiro; Xiao, Shiyu; Cai, Wenjie; Barajas, Sergio; Chen, Sisi; Miao, Jinmin; Nguele Meke, Frederick; Vemula, Sasidhar; Ropa, James P.; Croop, James M.; Boswell, H. Scott; Wan, Jun; Jia, Yuzhi; Liu, Huiping; Li, Loretta S.; Altman, Jessica K.; Eklund, Elizabeth A.; Ji, Peng; Tong, Wei; Band, Hamid; Huang, Danny T.; Platanias, Leonidas C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
    Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.
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    PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation
    (American Association for Cancer Research, 2024) Chen, Hongxia; Bai, Yunpeng; Kobayashi, Michihiro; Xiao, Shiyu; Barajas, Sergio; Cai, Wenjie; Chen, Sisi; Miao, Jinmin; Meke, Frederick Nguele; Yao, Chonghua; Yang, Yuxia; Strube, Katherine; Satchivi, Odelia; Sun, Jianmin; Rönnstrand, Lars; Croop, James M.; Boswell, H. Scott; Jia, Yuzhi; Liu, Huiping; Li, Loretta S.; Altman, Jessica K.; Eklund, Elizabeth A.; Sukhanova, Madina; Ji, Peng; Tong, Wei; Band, Hamid; Huang, Danny T.; Platanias, Leonidas C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
    Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. Implications: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.