Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewThe two faces of PTP1B in cancer
Introduction
Mediated by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), the appropriate control of protein tyrosine phosphorylation is essential for cellular homeostasis. The PTPs are not only counteracting the receptor tyrosine kinases (RTKs), but they also play a dominant role in the regulation of many physiological processes. In recent years, the protein tyrosine phosphatase 1B (PTP1B) has emerged as a critical regulator of multiple signaling networks involved in human disorders such as diabetes, obesity, and cancer. In this review, we will discuss the growing evidence for the role of PTP1B in cancer and specifically address the issue of whether PTP1B acts as a tumor suppressor or a tumor promoter.
Section snippets
Genomics of PTP1B
The PTP1B locus maps to human chromosome 20 in the region q13.1–q13.2 [1] and its mouse ortholog to the syntenic H2–H3 region of chromosome 2 [2]. Interestingly, this region in the mouse was also identified as a quantitative trait locus (QTL) linked to diabetes and obesity [3]. Consistent with a role for PTP1B in human insulin resistance, single nucleotide polymorphisms associated with diabetes have been found within the coding [4], [5] and 3′ UTR regions [6], [7]. The gain or amplification of
PTP1B substrates
PTP1B substrates are involved in multiple cellular processes such as glucose uptake, proliferation, differentiation, apoptosis, cell–cell adhesion, extracellular matrix attachment, motility and invasion (reviewed in [43]). They include RTKs, intracellular PTKs, adapter proteins, cytoskeletal proteins, and transcription factors. PTP1B-catalyzed phosphotyrosine removal may, in a substrate-dependent context, either inactivate or activate its substrate activities and correspondingly modulate their
Metabolic function of PTP1B
PTP1B is well established as a critical modulator of metabolic signaling in mammals. PTP1B null mice display enhanced sensitivity to insulin [4], [45]. This correlates with enhanced tyrosine phosphorylation of the IR in muscle, liver and brain. Moreover, ablation of PTP1B confers resistance to obesity induced by a high-fat diet [45]. PTP1B is also involved in leptin signaling, as seen with the decreased weight gain in leptin-deficient ob/ob mice lacking PTP1B when compared to control
PTP1B inhibitors
Following the landmark studies describing the metabolic phenotype of knockout mice, published in 1999, there was a surge of interest in PTP1B-targeted therapeutics among academic and industrial laboratories. At one point, small-molecule PTP1B inhibitors were being developed by > 10 pharmaceutical companies (reviewed in [63], [64], [65]), several of whom published papers describing comprehensive structural optimizations of lead compounds (e.g. [66], [67], [68]). A common strategy was to
PTP1B as a tumor suppressor
The dephosphorylation of substrates by PTP1B suggests that overexpression of the phosphatase should protect against transformation induced by constitutively active PTKs. Indeed, this hypothesis has been verified in v-src-expressing cells [24] and neu TM-transformed cells [79] where PTP1B overexpression diminishes tumorigenecity. Similarly, up-regulation of PTP1B expression prevents BCR-ABL-induced transformation of Rat-1 cells and promotes differentiation of BCR-ABL-expressing cells [80].
Conclusion and perspectives
Despite the increasing number of reports implicating PTP1B in cancer, we are far from understanding its exact role in tumorigenesis. As depicted in this review, one of the major concerns is whether this phosphatase acts as a tumor suppressor, a tumor promoter, or both. The latter possibility seems the most plausible and may depend on the type of tissue involved and/or the presence mutations in other cancer susceptibility genes. For instance, in vivo data suggest that PTP1B can repress, although
Acknowledgments
L.L. is a recipient of a Canadian Institutes of Health Research fellowship award. M.S. is a recipient of a Fonds de la recherche en santé du Québec doctoral award. M.L.T is a Chercheur National of the Fonds de Recherche en Santé du Québec. This work was supported by a Canadian Institutes of Health Research operating grant (MOP-62887) and a Jeanne and Jean-Louis Cancer Research Chair to M.L.T.
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