Revisiting histidine-dependent acid phosphatases: a distinct group of tyrosine phosphatases

Abstract

Although classical protein tyrosine phosphatase (PTP) superfamily members are cysteine-dependent, emerging evidence shows that many acid phosphatases (AcPs) function as histidine-dependent PTPs in vivo. These AcPs dephosphorylate phospho-tyrosine substrates intracellularly and could have roles in development and disease. In contrast to cysteine-dependent PTPs, they utilize histidine, rather than cysteine, for substrate dephosphorylation. Structural analyses reveal that active site histidine, but not cysteine, faces towards the substrate and functions as the phosphate acceptor. Nonetheless, during dephosphorylation, both histidine-dependent and cysteine-dependent PTPs use their active site arginine and aspartate for substrate binding and proton donation, respectively. Thus, we propose that they should be referred to as a distinct group of ‘histidine-dependent PTPs’ within the PTP superfamily.

Human Prostatic Acid Phosphatase, an Authentic Tyrosine Phosphatase, Dephosphorylates ErbB-2 and Regulates Prostate Cancer Cell Growth

“…cPAcP Regulates ErbB-2 Tyrosine Phosphorylation histidine-dependent tyrosine phosphatases play a critical role in regulating cell growth and differentiation (25 (45). The cPAcP dephosphorylation model supports the notion that dimeric cPAcP dephosphorylates two autophosphorylated residues on an activated receptor simultaneously because the presence of a second phosphorylated tyrosyl residue at the C terminus of ErbB-2 may considerably enhance the binding affinity (45 (Fig.…”

“…It is noted that cPAcP and secreted PAcP exhibit different biochemical properties including different isoelectric points and sensitivities to endoglycosidases (20). The function of cPAcP in growth regulation is at least in part contributed by its intrinsic PTP activity (20 -23), although it does not contain the signature motif, HCXXGXXR, found in cysteine-dependent PTPs (24,25). The overall tyrosyl phosphorylation level, the tyrosyl kinase specific activity, and the cell growth rate are inversely correlated with cPAcP activity in PCa cell lines under various growth conditions (26 -28).…”

Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor

“…Site-directed mutagenesis analyses showed His12 and Asp258, but not Cys183 or Cys281, are essential for the PTP activity of PAcP [71]. For the hydrolysis reaction, His12 and Asp258 of PAcP act as a phosphate acceptor and the proton donor, respectively [5,70,72,73]. It should also be noted Asp258 is conserved in the PTP family [5,70].…”

“…Structural, functional and sequence analyses have classified the PTP superfamily enzyme into (i) Class I cys-based PTPs including ‘classical tyrosine-specific’ and ‘dual specificity phosphatases (DSPs)’, (ii) Class II cys-based low molecular weight acid phosphatases, (iii) Class III cys-based CDC25 and (iv) Asp-based PTPs [2–4] and (v) His-based PTPs [5] (Table 1). Further, the ‘classical tyrosine-specific’ PTPs are divided into two subfamilies: the receptor-type PTP (RPTP), primarily localized at transmembrane region, and the nonreceptor-type PTP (NRPTPs), which localized in the cytosol.…”

“…In past, major efforts have been made on investigating Tyr-phosphorylation regulation of kinases in PCa. Recent advances have moved to search for prostate-specific PTPs and revealed approximately one hundred PTPs expressed in prostate tissue (Table 1) [3–5] in addition to eight ubiquitously known tumor suppressor genes (TSGs) (Rb, p53, PTEN, PP2A, PHLPP, APC, BRCA2 and WT1; Table 2) [14–45]. Further analyses of PTP expression and comparison of closely related PTPs have demonstrated their function to maintain prostate cell homeostasis and revealed cellular prostatic acid phosphatase (cPAcP) as a unique prostate-specific TSG.…”