Browsing by Author "Nguele Meke, Frederick"

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    Effects of siRNA-Mediated PRL2 Knockdowns on Cell Signaling in Pancreatic and Lung Cancer Cell Lines
    (2021-11-15) Ayub, Jinan; Nguele Meke, Frederick; Zhang, Zhong-Yin
    Phosphatase of regenerating liver (PRL) is an enzymatic phosphatase whose oncogenic properties warrant its investigation as a therapeutic drug target. Of all three variants, PRL2 is the most abundantly expressed in cells and dephosphorylates proteins involved in preventing oncogenesis. A recent publication by Dr. Zhong-Yin Zhang’s lab showed that PRL2 downregulates PTEN by dephosphorylating its Y336 residue, activating ubiquitin-mediated PTEN degradation and increasing the cell’s susceptibility to malignancies. This project investigated if lower PRL2 expression in pancreatic and lung cancer cell lines, which confer high mortality rates, can suppress its oncogenic effects in signaling pathways. In this study, five different pancreatic and lung cancer cell lines, PaCa2, A549, H358, HPAF, and CFPAC, were transiently transfected with small interfering RNA (siRNA) to knockdown PRL2 expression. After 48 hours, the protein expression of ERK/AKT, STAT3, PCNA, PTEN, and PARP in these cells were analyzed on Western blots. The preliminary results were mixed, with only the A549, H358, and PaCa2 cell lines showing the expected increase in PTEN levels. All cell lines showed increased apoptosis, as demonstrated by increased cleaved PARP levels. These results may help determine if disrupting PRL-regulated pathways can prevent pancreatic and lung cancer cell development. In the future, CRISPR-Cas9 will be used to generate PRL2 knockout stable lines, as the signaling studied under transient transfections may be too short-lived to accurately capture the effect of PRL2 loss on cell signaling. Additionally, experiments with mouse xenograft models will be performed to further evaluate tumorigenicity in vivo.
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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.