Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP

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PTP1B and TC-PTP are closely related protein tyrosine phosphatases, sharing 74% homology in their catalytic domain. However, their cellular localization, function, and regulation are found to be different. Their substrate specificity has implicated these enzymes in various signaling pathways, regulating metabolism, proliferation and cytokine signaling. For instance, PTP1B has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the JAK family, namely JAK2 and TYK2, whereas TC-PTP is involved in the modulation of cytokine signaling via JAK1 and JAK3 molecules. Gene-targeting approaches will help us to unravel the physiological functions of these enzymes.

Introduction

Tyrosine phosphorylation is well known to modulate a great number of key biological events. As important as tyrosine kinases, the protein tyrosine phosphatases (PTPs) have been associated with developmental processes as well as with diseases including cancer, diabetes, hyperlipidemia and inflammation. These recent associations between PTPs and diseases call for an examination of the general mechanism of PTP modulation and their corresponding function. With >100 different PTPs in the mammalian genome [1••], it becomes a formidable task to tackle all of them. The T-cell PTP (TC-PTP) and PTP1B enzymes are models used to examine gene regulation in PTPs, and as they are independent yet closely related they provide interesting examples of differential regulation and function. The present review focuses on these well-studied PTPs, examining their unique controlling elements and comparing their mechanisms of action and function.

Section snippets

PTP1B and TC-PTP: similar proteins, different localization

PTP1B, the prototype for the superfamily of PTPs, is described as a 435-amino-acid (aa) 50-kDa protein [2]. Its structure consists of an N-terminal catalytic domain (PTP domain) followed by two tandem proline-rich motifs that allow the interaction with SH3-domain-containing proteins. The closest homologue to PTP1B is TC-PTP. Human TC-PTP is described as an intracellular protein comprising 418 aa residues. A splicing event can generate two distinct mRNAs, termed TC-PTPa and TC-PTPb, with

Regulation of mRNA and protein expression

The expression of PTP1B is widely modulated in response to circumstances ranging from metabolic stresses to cellular transformation. Many reports showed increased expression and/or activity of PTP1B in insulin-resistant states and obesity [8, 9], notably in skeletal muscle and adipose tissue [10]. Furthermore, it has been shown that hepatic expression of PTP1B is increased in a fructose-fed hamster model of insulin resistance [11]. Related to this, we recently reported that hepatic levels of

Regulation of PTP1B and TC-PTP activity

The activity of PTPs is tightly regulated in vivo by oxidation and reduction reactions involving the invariant cysteine in the catalytic domain [20]. In insulin-sensitive hepatoma and adipose cells, insulin stimulation generates a burst of intracellular hydrogen peroxide (H2O2) that is associated with reversible oxidative inhibition of cellular PTP activity [21]. It was recently shown that insulin stimulation resulted in rapid and transient oxidation and inhibition of TC-PTP and PTP1B using an

Identification of downstream substrates

Substrate identification is a crucial step in delineating signaling pathways regulated by PTP1B and TC-PTP in vivo. To attain this goal, a substrate-trapping approach was employed to identify physiological targets of PTP1B and TC-PTP [20]. Catalytic domain mutations of PTP1B and TC-PTP (Asp→Ala [D/A] or Cys→Ser [C/S]) ablate the ability of the PTPs to dephosphorylate target substrates but do not affect substrate binding. These mutants can form stable enzyme–substrate complexes, allowing

PTP1B and TC-PTP: complementation or opposite roles

To better elucidate the physiological role of each of these two PTPs, null mutant mice were generated for TC-PTP and PTP1B using gene-targeting technology [29, 30, 31]. Mice bearing either null enzyme displayed different phenotypes, which indicates that these PTPs have distinct functions as described in Table 2.

The in vivo analysis of the mutant mice as well as an in vitro cellular approach indicated that PTP1B and TC-PTP could control cytokine signaling events by their negative action on the

EGFR and PDGFR

TC-PTP and PTP1B can control cellular proliferation via several pathways including growth factor receptors such as the epidermal growth factor (EGF) and the platelet-derived growth factor (PDGF). Overexpression studies, substrate-trapping approaches and fluorescence resonance energy transfer technique (FRET) have shown that PTP1B has a function in dephosphorylating the EGF receptor (EGFR) and the PDGF receptor (PDGFR) [20, 44, 45, 46, 47]. Genetic evidence was provided by the observation that

The insulin receptor

From the variety of PTPs found in insulin-sensitive tissues, PTP1B and TC-PTP are amongst the potential candidates for the regulation of the insulin signaling pathway (see Table 1). Indeed, targeted disruption of the PTP1B gene in mice led to tissue-specific increased insulin sensitivity, as well as resistance to diet-induced diabetes and obesity [30, 31]. Since the regulation of insulin signaling by PTP1B appears to be tissue-specific, other PTPs such as TC-PTP might complement the regulation

Conclusions

The study of TC-PTP and PTP1B enzymes provides us with several interesting findings that can be generalized to most of the subfamily of intracellular PTPs. Importantly, the study of TC-PTP and PTP1B is quite revealing on the generally broad nature of their substrates. For both of these enzymes, nearly a dozen interacting molecules have been identified, which complicates functional studies. However, it is still questionable if all of these substrates are physiologically relevant. Until recently,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Krista Heinonen for critical reading of the manuscript. AB is a recipient of a cancer immunology fellowship from the Cancer Research Institute of New York. ND is a recipient of a Canadian Institutes of Health Research doctoral award. MLT is a scientist of the Canadian Institutes of Health Research. This work has been supported by operating grants to MLT from the Canadian Institutes of Health Research (MOP-62887) and from the National Cancer Institute of Canada (015200).

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