Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I

Total Page:16

File Type:pdf, Size:1020Kb

Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I Published OnlineFirst January 13, 2017; DOI: 10.1158/1078-0432.CCR-16-0934 Molecular Pathways Clinical Cancer Research Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I. Savage, and Powel H. Brown Abstract The aberrant activation of oncogenic signaling pathways is a act as tumor suppressor genes by terminating signal responses universal phenomenon in cancer and drives tumorigenesis and through the dephosphorylation of oncogenic kinases. More malignant transformation. This abnormal activation of signal- recently, it has become clear that several PTPs overexpressed ing pathways in cancer is due to the altered expression of in human cancers do not suppress tumor growth; instead, they protein kinases and phosphatases. In response to extracellular positively regulate signaling pathways and promote tumor signals, protein kinases activate downstream signaling path- development and progression. In this review, we discuss both ways through a series of protein phosphorylation events, ulti- types of PTPs: those that have tumor suppressor activities as mately producing a signal response. Protein tyrosine phospha- well as those that act as oncogenes. We also discuss the tases (PTP) are a family of enzymes that hydrolytically remove potential of PTP inhibitors for cancer therapy. Clin Cancer Res; phosphate groups from proteins. Initially, PTPs were shown to 23(9); 1–7. Ó2017 AACR. Background in cancer and discuss the current status of PTP inhibitors for cancer therapy. Signal transduction is a complex process that transmits extra- PTPs belong to a superfamily of enzymes that hydrolytically cellular signals effectively through a cascade of events involving remove phosphate groups from proteins (2). Genome sequenc- protein phosphorylation/dephosphorylation to produce a broad ing studies have shown that the human genome includes more spectrum of signal responses. Protein phosphorylation, mediated than 100 genes that encode PTPs (3, 4). These enzymes func- by protein kinases, is a reversible posttranslational modification tion as holoenzymes and share a consensus sequence (known that leads to the activation of signal transduction pathways as the HCX R motif, where X is any amino acid) in the active involved in cell biological processes, such as growth, prolifera- 5 site of the enzyme (5). PTPs are classified on the basis of their tion, metabolism, differentiation, and cell death. Uncontrolled cellular localization, specificity, and function. Cellular locali- activation of these pathways results in abnormal cell growth and zation determines whether PTPs are grouped as receptor-type proliferation leading to tumorigenesis. Dephosphorylation of PTPs (PTPR), which are localized to the plasma membrane, or proteins is mediated by protein tyrosine phosphatases (PTP) that non-receptor–type PTPs (PTPN), which are localized in the lead to the termination of signaling pathways, resulting in the cytosol. Similarly, based on their specificity, PTPs are grouped inhibition of growth, proliferation, and differentiation. In normal into either tyrosine-specific phosphatases or dual-specificphos- cells, the balance between the activation and termination of phatases (which remove a phosphate group from tyrosine and/ signaling pathways is accomplished through coordination or serine/threonine residues). between these protein kinases and phosphatases, which subse- PTPs are broadly classified into two groups based on their quently controls the amplitude and duration of a signal response. function: tumor suppressor PTPs or oncogenic PTPs. These tumor Loss or disruption of the balance of signal pathways is implicated suppressor/oncogenic PTPs may belong to the other groups in many human diseases. Dysregulation of this balance in human described above based on their cellular localization and specificity. cancers is due to the hyperactivation of protein kinases or loss of The loss of tumor suppressor PTP function is often observed in PTPs, which dephosphorylate oncogenic protein kinases. Our cancer due to gene deletions, mutations, and epigenetic modifica- recent study was the first report to extensively profile the expres- tions, such as promoter methylation. Loss of these tumor suppres- sion of PTPs altered in human breast cancer samples (1). In this sor PTPs leads to the hyperactivation of signaling pathways and review, we will discuss tumor suppressor and oncogenic PTPs promotes tumorigenesis. PTEN is the most frequently mutated phosphatase, leading to hyperactivation of the PI3K signaling pathway in many human cancers. Similar to PTEN, underexpres- sion of inositol polyphosphate-5-phosphatase J (INPP5J) is Department of Clinical Cancer Prevention, The University of Texas MD Anderson observed in triple-negative breast cancer (TNBC), and increases Cancer Center, Houston, Texas. in vivo PI3K/Akt signaling and oncogene-induced transformation Corresponding Author: Powel H. Brown, Department of Clinical Cancer Pre- and tumor growth while reducing metastasis in mouse models (6). vention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1360, Houston, TX 77030. Phone: 713-792-4509; Fax: 713-794- 4679; E-mail: [email protected] Phosphatases as Tumor Suppressors doi: 10.1158/1078-0432.CCR-16-0934 Several tumor suppressor PTPs have been identified whose Ó2017 American Association for Cancer Research. loss has been shown to promote tumorigenesis, growth, and www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst January 13, 2017; DOI: 10.1158/1078-0432.CCR-16-0934 Bollu et al. Table 1. Tumor suppressor PTPs and cancer PTP Cancer Mechanism for reduced expression Altered signaling pathway Reference PTEN Prostate and breast Mutations and deletions PI3K 7–10 INPP5J Breast Transcriptional repression PI3K 2 SHP1 Leukemia and lymphomas Methylation of promoter JAK/STAT signaling 27, 28 DEP1 Breast and colon Mutations and deletions FLT3, Erk1/2, and Akt signaling 11, 12 PTPRF Colon, breast, and lung * Somatic mutations * PDGF, Akt, and PLC 17 PTPRG * Deletions * JAK and integrin PTPRT * Methylation of promoter regions * STAT3 and paxillin PTPN3 * EGFR/MAPK signaling PTPN13 * Src signaling PTPN14 * YAP signaling PTPN12 Breast Mutations EGFR, HER2, and mTOR 18 PTPRK Colon and lymphoma Methylation of promoter EGFR and Akt signaling 19, 20 DUSP6 Leukemia, lung, and liver Methylation of promoter MAPK signaling 27 DUSP4 Breast, pancreas, and thyroid Copy number loss MAPK, JNK, Rb, and NF-kB13–16 PTPRO Leukemia, lung, and breast Methylation of promoter P53/FOXM1 24–26 metastasis in in vitro and in vivo models (Table 1). The first tumor promotes the transformation of mammary epithelial cells suppressor phosphatase identified was PTEN, which was found to through activation of the EGFR/HER2 signaling axis (Table 1; be frequently lost or mutated in many human cancers at high ref. 18). In addition to gene deletions and inactivating mutations, frequency (reviewed in refs. 7, 8). PTEN dephosphorylates phos- loss of tumor suppressor PTP function may be due to loss of phoinositide substrates, which leads to inhibition of the AKT/PKB expression by epigenetic modifications in the promoter region. kinase cascade. Mutation or loss of PTEN results in unopposed Analysis of the methylation patterns of CpG islands within the activation of AKT, leading to growth promotion and tumor promoter regions has revealed that loss of PTPRF, PTPRM, and development. Laboratory studies have shown that deletion of PTPRK expression is due to hypermethylation in leukemia sam- PTEN in normal cells promotes transformation of these cells (9) ples (19). Loss of PTPRK leads to hyperactivation of Akt signaling and that PTEN-deficient mice develop cancers (10). and promotes colon cancer progression (20). PTPRK also func- More recently, other tumor suppressor phosphatases have been tions as a tumor suppressor by inhibiting the phosphorylation of identified. These include DEP1 [also known as PTP receptor EGFR (21) and STAT3, and subsequently inhibiting tumor growth (PTPR) type J] that is frequently deleted or mutated in many and invasive ability (22). human cancers, including breast and colon cancers (Table 1; Hypermethylation of promoter regions may suppress the ref. 11). Loss of DEP1 is associated with increased growth factor expression of several other tumor suppressor phosphatases. receptor signaling and promotes cell growth (12). Recently, Promoter methylation silences the expression of DUSP6 in Mazumdar and colleagues identified dual specificity phosphatase primary pancreatic cancers (23) and PTPRO in hepatocellular 4 (DUSP4) as the most commonly underexpressed protein phos- carcinoma, lung cancer, and leukemia (Table 1; ref. 24). À phatase in estrogen receptor–negative (ER ) breast cancers, and Overexpression of PTPRO induces antiproliferative/transfor- showed that ectopic expression of DUSP4 inhibits the growth and mational and apoptotic properties in leukemia and lung À invasive properties of ER breast cancer cells by dephosphorylat- cancer cells (25), and PTPRO promoter methylation is a þ ing growth-promoting signaling proteins (13). Similarly, loss of predictive marker for poor prognosis in HER2 breast cancer DUSP4 promotes the progression of intraepithelial neoplasms patients (26). Hypermethylation of the SHP1 (PTPN6) pro- into invasive carcinoma in the pancreas (14). Moreover, loss of moter has been reported in leukemias/lymphomas,
Recommended publications
  • Methylation and Silencing of Protein Tyrosine Phosphatase Receptor
    Human Cancer Biology Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic Leukemia Tasneem Motiwala,1Sarmila Majumder,1Huban Kutay,1David Spencer Smith,1Donna S. Neuberg,4 David M. Lucas,2 John C. Byrd,2,3 Michael Grever,2,3 and Samson T.Jacob1, 2 , 3 Abstract Purpose: Previous studies in our laboratory have shown the progressive methylation and suppression of the gene encoding protein tyrosine phosphatase, PTPRO, in the livers of rats fed a methyl-deficient diet that induces hepatocarcinogenesis. Subsequently, we observed the methylation of PTPRO in primary human lung tumors and also showed its potential tumor suppressor characteristics. The present study was undertaken to investigate whether the truncated form of PTPRO (PTPROt), specifically expressed in naI«ve B lymphocytes, was also methylated and suppressed in chronic lymphocytic leukemia (CLL), a disease generally affecting B lymphocytes. Experimental Design and Results: Initial screening showed that 60% of the 52 CLL samples analyzed using methylation-specific PCR assay were methylated compared with B lymphocytes from normal individuals, which were not methylated. The expression of PTPROt, as measured by semiquantitative reverse transcription-PCR, inversely correlated with methylation in the few samples tested. Analysis of additional samples (n = 50) by combined bisulfite restriction analysis showed that the PTPRO CpG island was methylated in 82% of patients with CLL compared with B lymphocytes from normal individuals. Furthermore, overall expression of PTPRO was reduced in CLL relative to normal lymphocytes. The PTPRO gene was also suppressed by methylation in the CLL cell lineWaC3CD5, where it could be reactivated upon treatment with the DNA hypome- thylating agent 5-AzaC.
    [Show full text]
  • Identification of Chebulinic Acid As a Dual Targeting Inhibitor of Protein
    Bioorganic Chemistry 90 (2019) 103087 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Short communication Identification of chebulinic acid as a dual targeting inhibitor of protein T tyrosine phosphatases relevant to insulin resistance Sun-Young Yoona,1, Hyo Jin Kangb,1, Dohee Ahna, Ji Young Hwanga, Se Jeong Kwona, ⁎ Sang J. Chunga, a School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea b Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea ARTICLE INFO ABSTRACT Keywords: Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the Protein tyrosine phosphatases (PTPs) protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as Chebulinic acid potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 Type 2 diabetes increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could Glucose-uptake be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 PTPN9 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding toPTPN9 PTPN11 (IC50 = 34 nM) and PTPN11 (IC50 = 37 nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAF -Mutant Melanoma Patient-Derived Xenografts
    Published OnlineFirst September 16, 2019; DOI: 10.1158/1535-7163.MCT-19-0028 Cancer Biology and Translational Studies Molecular Cancer Therapeutics Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAFV600-Mutant Melanoma Patient-Derived Xenografts Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David A. Ruddy, Daniel P. Rakiec, Felipe C. Geyer, Jane Gu, Hui Gao, Juliet A.Williams, Darrin D. Stuart, and Matthew J. Meyer Abstract Inhibitors targeting BRAF and its downstream kinase MEK are preferentially sensitive to MAPK inhibition. These gene- produce robust response in patients with advanced BRAFV600- expression programs are somewhat similar to the MITF-high mutant melanoma. However, the duration and depth of and -low phenotypes described in cancer cell lines, but response vary significantly between patients; therefore, pre- demonstrate an inverse relationship with drug response. dicting response a priori remains a significant challenge. Here, This suggests a discrepancy between in vitro and in vivo we utilized the Novartis collection of patient-derived xeno- experimental systems that warrants future investigations. grafts to characterize transcriptional alterations elicited by Finally, BRAFV600-mutant melanoma relies on either MAPK BRAF and MEK inhibitors in vivo, in an effort to identify or alternative pathways for survival under BRAF and MEK mechanisms governing differential response to MAPK inhibi- inhibition in vivo, which in turn predicts their response to tion. We show that the expression of an MITF-high, "epithelial- further pathway suppression using a combination of BRAF, like" transcriptional program is associated with reduced MEK, and ERK inhibitors. Our findings highlight the inter- sensitivity and adaptive response to BRAF and MEK inhibitor tumor heterogeneity in BRAFV600-mutant melanoma, and treatment.
    [Show full text]
  • Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase As a Molecular Target for Ovarian Cancer
    biomolecules Article Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer John S. Lazo 1,2,* , Elizabeth R. Sharlow 1,2,*, Robert Cornelison 1,2, Duncan J. Hart 1, Danielle C. Llaneza 1, Anna J. Mendelson 1, Ettore J. Rastelli 3 , Nikhil R. Tasker 3, Charles N. Landen, Jr. 4 and Peter Wipf 3 1 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; [email protected] (R.C.); [email protected] (D.J.H.); [email protected] (D.C.L.); [email protected] (A.J.M.) 2 KeViRx, Inc., Charlottesville, VA 22904, USA 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (E.J.R.); [email protected] (N.R.T.); [email protected] (P.W.) 4 Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USA; [email protected] * Correspondence: [email protected] or [email protected] (J.S.L.); [email protected] (E.R.S.); Tel.: +1-434-243-1936 (J.S.L.); +1-434-243-1937 (E.R.S.) Abstract: High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines Citation: Lazo, J.S.; Sharlow, E.R.; compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor Cornelison, R.; Hart, D.J.; Llaneza, and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of D.C.; Mendelson, A.J.; Rastelli, E.J.; JMS-053-based analogs in OvCa cell line-based phenotypic assays.
    [Show full text]
  • Supp Table 1.Pdf
    Upregulated genes in Hdac8 null cranial neural crest cells fold change Gene Symbol Gene Title 134.39 Stmn4 stathmin-like 4 46.05 Lhx1 LIM homeobox protein 1 31.45 Lect2 leukocyte cell-derived chemotaxin 2 31.09 Zfp108 zinc finger protein 108 27.74 0710007G10Rik RIKEN cDNA 0710007G10 gene 26.31 1700019O17Rik RIKEN cDNA 1700019O17 gene 25.72 Cyb561 Cytochrome b-561 25.35 Tsc22d1 TSC22 domain family, member 1 25.27 4921513I08Rik RIKEN cDNA 4921513I08 gene 24.58 Ofa oncofetal antigen 24.47 B230112I24Rik RIKEN cDNA B230112I24 gene 23.86 Uty ubiquitously transcribed tetratricopeptide repeat gene, Y chromosome 22.84 D8Ertd268e DNA segment, Chr 8, ERATO Doi 268, expressed 19.78 Dag1 Dystroglycan 1 19.74 Pkn1 protein kinase N1 18.64 Cts8 cathepsin 8 18.23 1500012D20Rik RIKEN cDNA 1500012D20 gene 18.09 Slc43a2 solute carrier family 43, member 2 17.17 Pcm1 Pericentriolar material 1 17.17 Prg2 proteoglycan 2, bone marrow 17.11 LOC671579 hypothetical protein LOC671579 17.11 Slco1a5 solute carrier organic anion transporter family, member 1a5 17.02 Fbxl7 F-box and leucine-rich repeat protein 7 17.02 Kcns2 K+ voltage-gated channel, subfamily S, 2 16.93 AW493845 Expressed sequence AW493845 16.12 1600014K23Rik RIKEN cDNA 1600014K23 gene 15.71 Cst8 cystatin 8 (cystatin-related epididymal spermatogenic) 15.68 4922502D21Rik RIKEN cDNA 4922502D21 gene 15.32 2810011L19Rik RIKEN cDNA 2810011L19 gene 15.08 Btbd9 BTB (POZ) domain containing 9 14.77 Hoxa11os homeo box A11, opposite strand transcript 14.74 Obp1a odorant binding protein Ia 14.72 ORF28 open reading
    [Show full text]
  • CDH12 Cadherin 12, Type 2 N-Cadherin 2 RPL5 Ribosomal
    5 6 6 5 . 4 2 1 1 1 2 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 A A A A A A A A A A A A A A A A A A A A C C C C C C C C C C C C C C C C C C C C R R R R R R R R R R R R R R R R R R R R B , B B B B B B B B B B B B B B B B B B B , 9 , , , , 4 , , 3 0 , , , , , , , , 6 2 , , 5 , 0 8 6 4 , 7 5 7 0 2 8 9 1 3 3 3 1 1 7 5 0 4 1 4 0 7 1 0 2 0 6 7 8 0 2 5 7 8 0 3 8 5 4 9 0 1 0 8 8 3 5 6 7 4 7 9 5 2 1 1 8 2 2 1 7 9 6 2 1 7 1 1 0 4 5 3 5 8 9 1 0 0 4 2 5 0 8 1 4 1 6 9 0 0 6 3 6 9 1 0 9 0 3 8 1 3 5 6 3 6 0 4 2 6 1 0 1 2 1 9 9 7 9 5 7 1 5 8 9 8 8 2 1 9 9 1 1 1 9 6 9 8 9 7 8 4 5 8 8 6 4 8 1 1 2 8 6 2 7 9 8 3 5 4 3 2 1 7 9 5 3 1 3 2 1 2 9 5 1 1 1 1 1 1 5 9 5 3 2 6 3 4 1 3 1 1 4 1 4 1 7 1 3 4 3 2 7 6 4 2 7 2 1 2 1 5 1 6 3 5 6 1 3 6 4 7 1 6 5 1 1 4 1 6 1 7 6 4 7 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m
    [Show full text]
  • The Regulatory Roles of Phosphatases in Cancer
    Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW The regulatory roles of phosphatases in cancer J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues.
    [Show full text]
  • Curcumin Alters Gene Expression-Associated DNA Damage, Cell Cycle, Cell Survival and Cell Migration and Invasion in NCI-H460 Human Lung Cancer Cells in Vitro
    ONCOLOGY REPORTS 34: 1853-1874, 2015 Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro I-TSANG CHIANG1,2, WEI-SHU WANG3, HSIN-CHUNG LIU4, SU-TSO YANG5, NOU-YING TANG6 and JING-GUNG CHUNG4,7 1Department of Radiation Oncology, National Yang‑Ming University Hospital, Yilan 260; 2Department of Radiological Technology, Central Taiwan University of Science and Technology, Taichung 40601; 3Department of Internal Medicine, National Yang‑Ming University Hospital, Yilan 260; 4Department of Biological Science and Technology, China Medical University, Taichung 404; 5Department of Radiology, China Medical University Hospital, Taichung 404; 6Graduate Institute of Chinese Medicine, China Medical University, Taichung 404; 7Department of Biotechnology, Asia University, Taichung 404, Taiwan, R.O.C. Received March 31, 2015; Accepted June 26, 2015 DOI: 10.3892/or.2015.4159 Abstract. Lung cancer is the most common cause of cancer CARD6, ID1 and ID2 genes, associated with cell survival and mortality and new cases are on the increase worldwide. the BRMS1L, associated with cell migration and invasion. However, the treatment of lung cancer remains unsatisfactory. Additionally, 59 downregulated genes exhibited a >4-fold Curcumin has been shown to induce cell death in many human change, including the DDIT3 gene, associated with DNA cancer cells, including human lung cancer cells. However, the damage; while 97 genes had a >3- to 4-fold change including the effects of curcumin on genetic mechanisms associated with DDIT4 gene, associated with DNA damage; the CCPG1 gene, these actions remain unclear. Curcumin (2 µM) was added associated with cell cycle and 321 genes with a >2- to 3-fold to NCI-H460 human lung cancer cells and the cells were including the GADD45A and CGREF1 genes, associated with incubated for 24 h.
    [Show full text]
  • The PTPRT Pseudo-Phosphatase Domain Is a Denitrase
    bioRxiv preprint doi: https://doi.org/10.1101/238980; this version posted December 22, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The PTPRT pseudo-phosphatase domain is a denitrase Yiqing Zhao1,2,#, Shuliang Zhao3,1,#, Yujun Hao1,2, Benlian Wang4, Peng Zhang1,2, Xiujing Feng1,2, Yicheng Chen1,2, Jing Song4, John Mieyal5, Sanford Markowitz1,2,6,7, Rob M. Ewing8,4, Ronald A. Conlon1,2, Masaru Miyagi4 and Zhenghe Wang1,2* 1Department of Genetics and Genome Sciences, 2Case Comprehensive Cancer Center, 4Department of Nutrition and Center for Proteomics and Bioinformatics, 5Department of Pharmacology, 6Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. 3Division of Gastroenterology and Hepatology and Shanghai Institution of Digestive Disease; Shanghai Jiao-Tong University School of Medicine Renji Hospital, 145 Middle Shandong Rd, Shanghai 200001, China. 7Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106. 8Computational and Systems Biology, School of Biological Sciences, University of Southampton, Southampton SO171BJ, UK * To whom correspondence should be addressed. Email: [email protected] # These authors contributed equally. bioRxiv preprint doi: https://doi.org/10.1101/238980; this version posted December 22, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Protein tyrosine nitration occurs under both physiological and pathological conditions1. However, enzymes that remove this protein modification have not yet been identified. Here we report that the pseudo-phosphatase domain of protein tyrosine receptor T (PTPRT) is a denitrase that removes nitro-groups from tyrosine residues in paxillin.
    [Show full text]
  • Bortezomib Inhibits Lung Fibrosis and Fibroblast Activation Without Proteasome
    bioRxiv preprint doi: https://doi.org/10.1101/2021.02.26.433086; this version posted February 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome 2 inhibition 3 4 Loka Raghu Kumar Penke, Jennifer Speth, Scott Wettlaufer, Christina Draijer and Marc 5 Peters-Golden1* 6 7 Affiliations 8 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, 9 University of Michigan, Ann Arbor, Michigan, USA. 10 1 Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA. 11 12 Correspondence: 13 Marc Peters-Golden, M.D. 14 6301 MSRBIII, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5642 15 Tel: 734-936-5047 16 Fax: 734-764-4556 17 Email: [email protected] 18 Author Contributions: L.R.K.P. planned and performed experiments, analyzed the 19 data, organized data for presentation, and wrote the manuscript. J.M.S, S.H.W and C.D 20 performed experiments. M.P.-G. planned experiments, analyzed data, and wrote the 21 manuscript. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.26.433086; this version posted February 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]
  • Genetic Alterations of Protein Tyrosine Phosphatases in Human Cancers
    Oncogene (2015) 34, 3885–3894 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Genetic alterations of protein tyrosine phosphatases in human cancers S Zhao1,2,3, D Sedwick3,4 and Z Wang2,3 Protein tyrosine phosphatases (PTPs) are enzymes that remove phosphate from tyrosine residues in proteins. Recent whole-exome sequencing of human cancer genomes reveals that many PTPs are frequently mutated in a variety of cancers. Among these mutated PTPs, PTP receptor T (PTPRT) appears to be the most frequently mutated PTP in human cancers. Beside PTPN11, which functions as an oncogene in leukemia, genetic and functional studies indicate that most of mutant PTPs are tumor suppressor genes. Identification of the substrates and corresponding kinases of the mutant PTPs may provide novel therapeutic targets for cancers harboring these mutant PTPs. Oncogene (2015) 34, 3885–3894; doi:10.1038/onc.2014.326; published online 29 September 2014 INTRODUCTION tyrosine/threonine-specific phosphatases. (4) Class IV PTPs include Protein tyrosine phosphorylation has a critical role in virtually all four Drosophila Eya homologs (Eya1, Eya2, Eya3 and Eya4), which human cellular processes that are involved in oncogenesis.1 can dephosphorylate both tyrosine and serine residues. Protein tyrosine phosphorylation is coordinately regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases 1 THE THREE-DIMENSIONAL STRUCTURE AND CATALYTIC (PTPs). Although PTKs add phosphate to tyrosine residues in MECHANISM OF PTPS proteins, PTPs remove it. Many PTKs are well-documented oncogenes.1 Recent cancer genomic studies provided compelling The three-dimensional structures of the catalytic domains of evidence that many PTPs function as tumor suppressor genes, classical PTPs (RPTPs and non-RPTPs) are extremely well because a majority of PTP mutations that have been identified in conserved.5 Even the catalytic domain structures of the dual- human cancers are loss-of-function mutations.
    [Show full text]