Prostate Cancer Dephosphorylation Atlas

The widespread nature of protein phosphorylation/dephosphorylation underscores its key role in cell metabolism. Phosphate moiety balance on proteins is regulated by protein kinases (PK) and protein phosphatases (PP), which are milestone players of eukaryotic signaling pathways. In general, signaling proteins involved in intracellular pathways are transiently active or inactive by phosphorylation and dephosphorylation mechanisms, covalently executed by PK and PP, respectively (Hooft et al. 2002; Tonks, 2005). It is accepted that the phosphorylation state of these proteins must be kept at a dynamic equilibrium in biological systems. Any deviation in this balance (generally associated with augmented PK signaling) can cause the intracellular accumulation of serine, threonine, tyrosine-phosphorylated proteins, which will cause abnormal cell proliferation and differentiation, thereby resulting in different kinds of diseases (Souza et al., 2009). Similar deviation from this equilibrium can be also induced by decreased activity of protein tyrosine phosphatases (PTP) resulting from gene mutation or gene deletion, leading to an increase in tyrosine phosphorylated proteins in cells. PPs are subdivided into two major families, with regard to their physiological substrates: protein tyrosine phosphatases and serine/threonine phosphatases. In particular, tyrosine phosphorylation of key proteins is a critical event in the regulation of intracellular signaling pathways (Aoyama et al., 2003; Gee and Mansuy, 2004; Souza et al., 2009). There is strong evidence pointing that low SHP-1 PTP activity is associated with a high proliferation rate and an increased risk of recurrence after radical prostatectomy for localized prostate cancer (Tassidis et al., 2010). Moreover, it has been proposed that specific PTPs may be related to determining the developmental stage and aggressiveness degree of prostate cancer (Chuang et al, 2010). Thus, it is reasonable to suggest that the chemical modulation of PTPs may, therefore, be a good spot for pharmacological intervention for overcoming prostate cancer, in combination with conventional cancer chemotherapeutic strategies. However, the critical bottleneck in deciphering the role of PTPs in prostate cancer biology is the identification of their physiological substrates and how their enzymatic activity is related to molecular changes in proliferation and cell death. In this chapter we shall focus on the contribution of the low molecular weight protein tyrosine phosphatase (LMWPTP), Src homology 2 (SH2) domaincontaining PTP (SHP-1), cell division cycle 25 (Cdc25), acid phosphatase, phosphatase and tensin homolog (PTEN) and dual-specificity phosphatase (DUSP) for prostate carcinogenesis and describe their participation in the molecular events that lead to tumor survival and