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

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Molecular Pathways: 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 26, 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,
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