Protein Tyrosine Phosphatases in Cancer: Friends and Foes!

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Tyrosine phosphorylation of proteins serves as an exquisite switch in controlling several key oncogenic signaling pathways involved in cell proliferation, apoptosis, migration, and invasion. Since protein tyrosine phosphatases (PTPs) counteract protein kinases by removing phosphate moieties on target proteins, one may intuitively think that PTPs would act as tumor suppressors. Indeed, one of the most described PTPs, namely, the phosphatase and tensin homolog (PTEN), is a tumor suppressor. However, a growing body of evidence suggests that PTPs can also function as potent oncoproteins. In this chapter, we provide a broad historical overview of the PTPs, their mechanism of action, and posttranslational modifications. Then, we focus on the dual properties of classical PTPs (receptor and nonreceptor) and dual-specificity phosphatases in cancer and summarize the current knowledge of the signaling pathways regulated by key PTPs in human cancer. In conclusion, we present our perspective on the potential of these PTPs to serve as therapeutic targets in cancer.

Introduction

Regulated protein phosphorylation is an evolutionarily conserved means of intra- and intercellular communication. While regulated phosphorylation of serine (pSer) and threonine (pThr) residues arose among the first single-celled eukaryotes, phosphotyrosine (pTyr) base signal transduction emerged later in evolution, coincident with the evolution of multicellular animals. In fact, the tyrosine signaling system has been proposed to be a critical event in evolution that enabled the expansion of multicellular species. Indeed, tyrosine phosphorylation is required for the activation of signaling pathways that regulate a plethora of important cellular activities, such as cell growth, hormone response, immune defense, and many others.1

Transduction of pTyr signaling requires two classes of enzymes: tyrosine kinases (TyrKs), which phosphorylate tyrosine residues; and protein tyrosine phosphatases (PTPs), which removes phosphate moieties. Although there are a handful of PTPs present in S. cerevisiae, the human “PTPome” contain 107 PTPs, which are grouped into four families based on the amino acid sequence of their catalytic domains. Almost all PTPs are part of the Class I cysteine-based family (99 genes), which includes the 38 classical PTPs (receptor-like PTPs (RPTPs, 21 genes)), nonreceptor-like PTPs (NRPTPs, 17 genes), and the dual-specificity phosphatases (DSPs, 61 genes).2 They share a common fold and the same HC(X)5R catalytic motif. Class II and Class III families are also cysteine-based PTPs and they include the low-molecular-weight PTP (LMPTP) and the three Cdc25 proteins, respectively. Finally, Asp-based PTPs represent the last family in which there are four EYA.2

Any changes in the expression or activities of these enzymes might tip the balance of cellular homeostasis and contribute positively or negatively to various diseases such as cancer. However, as the PTP field is expanding rapidly, this chapter cannot cover all aspects of PTP biology in cancer. For complementary information on the genetics and/or epigenetic alterations of PTP genes, refer to Julien et al.3 More detailed information on the expression of Class I PTP members in various cancer tissues4 and on the DSPs in human cancers5 was described elsewhere. Herein, the oncogenic activity of the 38 classical pTyr-specific PTPs is discussed in the context of human cancer cell lines and animal models. We also cover the DSP subgroup that can dephosphorylate pTyr-, pSer-, and pThr-containing substrates.

Section snippets

PTPs and Their Mechanism of Action

Tyrosine phosphorylation was first reported in 1978 in conjunction with the identification of the first TyrK, namely, Src.6, 7 The demonstration of an opposing regulator, however, required an additional decade of research. Initial studies involved the purification, characterization, and cloning of the prototypic PTP family member PTP1B by Nick Tonks and colleagues8, 9, 10 and a year later by the laboratory of Jack Dixon (Fig. 1).11 In 1994, the crystal structure of PTP1B was reported, resolving

Posttranslational Modifications of PTPs

Classical PTPs and DSPs share the same mechanism of action to achieve dephosphorylation of pTyr residues, yet they all demonstrate substrate specificity through various mechanisms. PTPs present different expression levels in organs, tissues, and cell types.34 Subcellular localization also regulates PTP specificity. While RPTPs are localized at the plasma membrane and NRPTPs and DSPs are primarily in the cytoplasm, PTPs can also reside in different subcellular compartments including the membrane

PTPs as Tumor Suppressors

TyrKs were discovered a decade before PTPs and many of them were found to be oncoproteins.116 Early on, many attempts were made to better understand the role of TyrKs in carcinogenesis117 and develop to drug treatments.118 Therefore, when PTPs were revealed later on as being the natural counterpart of TyrKs, it was assumed that they would act as tumor suppressors. This speculation took nearly a decade to be proven in human cancers. Identified in 1997, PTEN was classified as a putative tumor

Role of “oncoPTPs” in Cancer

Tyrosine phosphorylation does have a variety of effects that are not limited to activation of target proteins. In fact, tyrosine phosphorylation might do the complete opposite. An example is the cytosolic TyrK Src that is regulated through phosphorylation on Tyr529 at its C-terminal tail by the C-terminal Src kinase (Csk) or the Csk homologous kinase. When phosphorylated on this tyrosine residue, the Src oncogene is kept in a basal inactive state only to be activated following

Therapeutic Tools Targeting the Tyrosine Phosphatases

As we write this chapter, it is important to note that the development of small inhibitors of selected PTPs has proven to be a very difficult process for many individual medicinal teams across the world. Aside from the relative success made using antisense oligonucleotides against PTP1B mRNA in phase two clinical trials (Earlier Phase 2 studies of ISIS 113715, and a novel generation of PTP1B antisense (ISIS-PTP1BRx) that is just starting phase 1) (Fig. 3A), small molecular inhibitors have not

Conclusions and Perspectives

Much has been revealed in the last decade concerning the role of PTPs in cancer (Fig. 1). Though at the beginning as simple caretakers in response to TyrK activity, PTPs arise as key players in the carcinogenesis process. Their mutation, deletion, or overexpression can have great consequenses on cellular homeostasis and can drive tumorigenesis. Although many PTPs are potential therapeutical targets in cancer, the conserved motif among the PTP superfamily is a significant hurdle in the

Acknowledgments

The authors regret that, owing to space limitation, the work of many investigators who have contributed to define the role of PTPs in cancer had to be omitted. We thank Joseph J. Bowden and Kelly Pike for a critical review of the manuscript and Noriko Uetani for technical assistance with figure design and drawing. DPL is a recipient of a CIHR Frederick Banting and Charles Best Doctoral Research Award. MLT is the holder of the Jeanne and Jean-Louis Levesque Chair in Cancer Research.

References (349)

  • H.J. Nam et al.

    Crystal structure of the tandem phosphatase domains of RPTP LAR

    Cell

    (1999)
  • J. Zhang et al.

    Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis

    Cell Metab

    (2011)
  • J.V. Frangioni et al.

    The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence

    Cell

    (1992)
  • Y. Wang et al.

    Phosphorylation of CD45 by casein kinase 2. Modulation of activity and mutational analysis

    J Biol Chem

    (1999)
  • X.M. Zheng et al.

    Mitotic activation of protein-tyrosine phosphatase alpha and regulation of its Src-mediated transforming activity by its sites of protein kinase C phosphorylation

    J Biol Chem

    (2002)
  • T. Uchida et al.

    Insulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domains

    J Biol Chem

    (1994)
  • K. Yoshida et al.

    Functional interaction between SHPTP1 and the Lyn tyrosine kinase in the apoptotic response to DNA damage

    J Biol Chem

    (1999)
  • J. Tao et al.

    Insulin stimulates tyrosine phosphorylation and inactivation of protein-tyrosine phosphatase 1B in vivo

    J Biol Chem

    (2001)
  • J. Su et al.

    Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2

    J Biol Chem

    (1994)
  • H. Falet et al.

    Tyrosine unphosphorylated platelet SHP-1 is a substrate for calpain

    Biochem Biophys Res Commun

    (1998)
  • M. Gu et al.

    The properties of the protein tyrosine phosphatase PTPMEG

    J Biol Chem

    (1996)
  • H. Gil-Henn et al.

    Regulation of protein-tyrosine phosphatases alpha and epsilon by calpain-mediated proteolytic cleavage

    J Biol Chem

    (2001)
  • S.K. Rupinder et al.

    Cell suicide and caspases

    Vascul Pharmacol

    (2007)
  • S. Kamhawi

    Phlebotomine sand flies and Leishmania parasites: friends or foes?

    Trends Parasitol

    (2006)
  • M. Halle et al.

    The Leishmania surface protease GP63 cleaves multiple intracellular proteins and actively participates in p38 mitogen-activated protein kinase inactivation

    J Biol Chem

    (2009)
  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • Y.Y. Chen et al.

    Cysteine S-nitrosylation protects protein-tyrosine phosphatase 1B against oxidation-induced permanent inactivation

    J Biol Chem

    (2008)
  • K.I. Kim et al.

    SUMOylation code in cancer development and metastasis

    Mol Cells

    (2006)
  • T. Fukada et al.

    The reciprocal role of Egr-1 and Sp family proteins in regulation of the PTP1B promoter in response to the p210 Bcr-Abl oncoprotein-tyrosine kinase

    J Biol Chem

    (2001)
  • J.M. Zabolotny et al.

    Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo

    J Biol Chem

    (2008)
  • J.M. Desterro et al.

    SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation

    Mol Cell

    (1998)
  • T. Magee et al.

    Fatty acylation and prenylation of proteins: what's hot in fat

    Curr Opin Cell Biol

    (2005)
  • M. Pechlivanis et al.

    Hydrophobic modifications of Ras proteins by isoprenoid groups and fatty acids—more than just membrane anchoring

    Biochim Biophys Acta

    (2006)
  • Q. Zeng et al.

    Prenylation-dependent association of protein-tyrosine phosphatases PRL-1, -2, and -3 with the plasma membrane and the early endosome

    J Biol Chem

    (2000)
  • S.G. Julien et al.

    Inside the human cancer tyrosine phosphatome

    Nat Rev Cancer

    (2011)
  • S. Hardy et al.

    Impact of oncogenic protein tyrosine phosphatases in cancer

    Anticancer Agents Med Chem

    (2011)
  • C. Nunes-Xavier et al.

    Dual-specificity MAP kinase phosphatases as targets of cancer treatment

    Anticancer Agents Med Chem

    (2011)
  • M.S. Collett et al.

    Protein kinase activity associated with the avian sarcoma virus src gene product

    Proc Natl Acad Sci USA

    (1978)
  • H. Charbonneau et al.

    Human placenta protein-tyrosine-phosphatase: amino acid sequence and relationship to a family of receptor-like proteins

    Proc Natl Acad Sci USA

    (1989)
  • K.L. Guan et al.

    Cloning and expression of a protein-tyrosine-phosphatase

    Proc Natl Acad Sci USA

    (1990)
  • D. Barford et al.

    Crystal structure of human protein tyrosine phosphatase 1B

    Science

    (1994)
  • A.J. Flint et al.

    Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases

    Proc Natl Acad Sci USA

    (1997)
  • J. Li et al.

    PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer

    Science

    (1997)
  • P.A. Steck et al.

    Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers

    Nat Genet

    (1997)
  • S. Saha et al.

    A phosphatase associated with metastasis of colorectal cancer

    Science

    (2001)
  • C.A. Ruivenkamp et al.

    Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers

    Nat Genet

    (2002)
  • J.J. Fiordalisi et al.

    PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility

    Cancer Res

    (2006)
  • M.M. Tanner et al.

    Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer

    Cancer Res

    (1996)
  • M. Kleppe et al.

    Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia

    Nat Genet

    (2010)
  • J. Huang et al.

    Activation of Src and transformation by an RPTPalpha splice mutant found in human tumours

    EMBO J

    (2011)

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