Browsing by Author "Bai, Yunpeng"

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    Access provided by IUPUI University Library, Indiana (Ruth Lilly) Altmetric: 0Citations: 2More detail Letter to the Editor Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia
    (Nature, 2017) Kobayashi, Michihiro; Chen, Sisi; Bai, Yunpeng; Yao, Chonghua; Gao, Rui; Sun, Xiao-Jian; Mu, Chen; Twiggs, Taylor A.; Yu, Zhi-Hong; Boswell, H. Scott; Yoder, Mervin C.; Kapur, Reuben; Mulloy, James C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
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    Diversity-Oriented Synthesis for Novel, Selective and Drug-like Inhibitors for a Phosphatase from Mycobacterium Tuberculosis
    (Royal Society of Chemistry, 2014-10) He, Rongjun; Bai, Yunpeng; Yu, Zhi-Hong; Wu, Li; Gunawan, Andrea Michelle; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Mycobacterium protein tyrosine phosphatase B (mPTPB) is a potential drug target of Tuberculosis (TB). Small molecule inhibitors of mPTPB could be a treatment to overcome emerging TB drug resistance. Using a Diversity-Oriented Synthesis (DOS) strategy, we successfully developed a salicylic acid based and drug-like mPTPB inhibitor with an IC50 of 2 μM and >20-fold specificity over many human PTPs, making it an excellent lead molecule for anti-TB drug discovery. In addition, DOS generated bicyclic salicylic acids are also promising starting points for acquiring inhibitors targeting other PTPs.
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    Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta
    (Mary Ann Liebert, Inc., 2014-05-10) Zeng, Li-Fan; Zhang, Ruo-Yu; Bai, Yunpeng; Wu, Li; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    AIMS: Protein tyrosine phosphatases (PTPs) play an important role in regulating a wide range of cellular processes. Understanding the role of PTPs within these processes has been hampered by a lack of potent and selective PTP inhibitors. Generating potent and selective probes for PTPs remains a significant challenge because of the highly conserved and positively charged PTP active site that also harbors a redox-sensitive Cys residue. RESULTS: We describe a facile method that uses an appropriate hydroxyindole carboxylic acid to anchor the inhibitor to the PTP active site and relies on the secondary binding elements introduced through an amide-focused library to enhance binding affinity for the target PTP and to impart selectivity against off-target phosphatases. Here, we disclose a novel series of hydroxyindole carboxylic acid-based inhibitors for receptor-type tyrosine protein phosphatase beta (RPTPβ), a potential target that is implicated in blood vessel development. The representative RPTPβ inhibitor 8b-1 (L87B44) has an IC50 of 0.38 μM and at least 14-fold selectivity for RPTPβ over a large panel of PTPs. Moreover, 8b-1 also exhibits excellent cellular activity and augments growth factor signaling in HEK293, MDA-MB-468, and human umbilical vein endothelial cells. INNOVATION: The bicyclic salicylic acid pharmacophore-based focused library approach may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. CONCLUSION: A novel method is described for the development of bioavailable PTP inhibitors that utilizes bicyclic salicylic acid to anchor the inhibitors to the active site and peripheral site interactions to enhance binding affinity and selectivity.
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    Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase
    (AACR Publications, 2016-08-15) Bai, Yunpeng; Yu, Zhi-Hong; Liu, Sijiu; Zhang, Lujuan; Zhang, Ruo-Yu; Zeng, Li-Fan; Zhang, Sheng; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    PRL oncoproteins are phosphatases overexpressed in numerous types of human cancer. Elevated levels of PRL associate with metastasis and poor clinical outcomes. In principle, PRL phosphatases offer appealing therapeutic targets, but they remain underexplored due to the lack of specific chemical probes. In this study, we address this issue by exploiting a unique property of PRL phosphatases, namely, that they may function as homotrimers. Starting from a sequential structure-based virtual screening and medicinal chemistry strategy, we identified Cmpd-43 and several analogs which disrupt PRL1 trimerization. Biochemical and structural analyses demonstrate that Cmpd-43 and its close analogs directly bind the PRL1 trimer interface and obstruct PRL1 trimerization. Cmpd-43 also specifically blocks the PRL1-induced cell proliferation and migration through attenuation of both ERK1/2 and Akt activity. Importantly, Cmpd-43 exerted potent anticancer activity both in vitro and in vivo in a murine xenograft model of melanoma. Our results validate a trimerization-dependent signaling mechanism for PRL and offer proof-of-concept for trimerization inhibitors as candidate therapeutics to treat PRL-driven cancers
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    Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis
    (ASBMB, 2014-02-07) Dong, Yuanshu; Zhang, Lujuan; Bai, Yunpeng; Zhou, Hong-Ming; Campbell, Amanda M.; Chen, Hanying; Yong, Weidong; Zhang, Wenjun; Zeng, Qi; Shou, Weinian; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The Phosphatase of Regenerating Liver (PRL) proteins promote cell signaling and are oncogenic when overexpressed. However, our understanding of PRL function came primarily from studies with cultured cell lines aberrantly or ectopically expressing PRLs. To define the physiological roles of the PRLs, we generated PRL2 knock-out mice to study the effects of PRL deletion in a genetically controlled, organismal model. PRL2-deficient male mice exhibit testicular hypotrophy and impaired spermatogenesis, leading to decreased reproductive capacity. Mechanistically, PRL2 deficiency results in elevated PTEN level in the testis, which attenuates the Kit-PI3K-Akt pathway, resulting in increased germ cell apoptosis. Conversely, increased PRL2 expression in GC-1 cells reduces PTEN level and promotes Akt activation. Our analyses of PRL2-deficient animals suggest that PRL2 is required for spermatogenesis during testis development. The study also reveals that PRL2 promotes Kit-mediated PI3K/Akt signaling by reducing the level of PTEN that normally antagonizes the pathway. Given the strong cancer susceptibility to subtle variations in PTEN level, the ability of PRL2 to repress PTEN expression qualifies it as an oncogene and a novel target for developing anti-cancer agents.
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    Phosphatase of regenerating liver 3 (PRL3) provokes a tyrosine phosphoproteome to drive prometastatic signal transduction
    (ASBMB, 2013-09-12) Walls, Chad D.; Iliuk, Anton; Bai, Yunpeng; Wang, Mu; Tao, W. Andy; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Phosphatase of regenerating liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when in excess. To date, the molecular basis for PRL3 function remains an enigma, making efforts at distilling a concerted mechanism for PRL3-mediated metastatic dissemination very difficult. We previously discovered that PRL3 expressing cells exhibit a pronounced increase in protein tyrosine phosphorylation. Here we take an unbiased mass spectrometry-based approach toward identifying the phosphoproteins exhibiting enhanced levels of tyrosine phosphorylation with a goal to define the "PRL3-mediated signaling network." Phosphoproteomic data support intracellular activation of an extensive signaling network normally governed by extracellular ligand-activated transmembrane growth factor, cytokine, and integrin receptors in the PRL3 cells. Additionally, data implicate the Src tyrosine kinase as the major intracellular kinase responsible for "hijacking" this network and provide strong evidence that aberrant Src activation is a major consequence of PRL3 overexpression. Importantly, the data support a PDGF(α/β)-, Eph (A2/B3/B4)-, and Integrin (β1/β5)-receptor array as being the predominant network coordinator in the PRL3 cells, corroborating a PRL3-induced mesenchymal-state. Within this network, we find that tyrosine phosphorylation is increased on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, STAT, and ERK activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives prometastatic molecular events through Src activation.
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    Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies
    (Landes Bioscience, 2014) Kobayashi, Michihiro; Chen, Sisi; Gao, Rui; Bai, Yunpeng; Zhang, Zhong-Yin; Liu, Yan; Department of Pediatrics, IU School of Medicine
    The phosphatases of regenerating liver (PRLs), consisting PRL1, PRL2 and PRL3, are dual-specificity protein phosphatases that have been implicated as biomarkers and therapeutic targets in several solid tumors. However, their roles in hematological malignancies are largely unknown. Recent findings demonstrate that PRL2 is important for hematopoietic stem cell self-renewal and proliferation. In addition, both PRL2 and PRL3 are highly expressed in some hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Moreover, PRL deficiency impairs the proliferation and survival of leukemia cells through regulating oncogenic signaling pathways. While PRLs are potential novel therapeutic targets in hematological malignancies, their exact biological function and cellular substrates remain unclear. This review will discuss how PRLs regulate hematopoietic stem cell behavior, what signaling pathways are regulated by PRLs, and how to target PRLs in hematological malignancies. An improved understanding of how PRLs function and how they are regulated may facilitate the development of PRL inhibitors that are effective in cancer treatment.
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    Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia
    (Nature Publishing group, 2017-06) Kobayashi, Michihiro; Chen, Sisi; Bai, Yunpeng; Yao, Chonghua; Gao, Rui; Sun, Xiao-Jian; Mu, Chen; Twiggs, Taylor A.; Yu, Zhi-Hong; Boswell, H. Scott; Yoder, Mervin C.; Kapur, Reuben; Mulloy, James C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
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    Phosphatase PRL2 promotes oncogenic NOTCH1-Induced T-cell leukemia
    (Nature, 2017) Kobayashi, Michihiro; Bai, Yunpeng; Chen, Sisi; Gao, Rui; Yao, Chonghua; Cai, Wenjing; Cardoso, Angelo A.; Croop, James; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
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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.