Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues

Zhang, Xiau-Qun; Sundh, Ulla Beckman; Jansson, Leif; Zetterqvist, Örjan; Ek, Pia

doi:10.1080/03009730802642337

Cited by 14 publications

(22 citation statements)

References 13 publications

(23 reference statements)

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“…A 14 kDa enzyme capable of reversing pHis was purified in 2002 and thus the human phosphohistidine phosphatase (PHPT1) gene, encoding the enzyme could be identified (Ek et al, 2002, Klumpp et al, 2002. The PHPT1 protein is ubiquitously expressed in mammalian cells (Zhang et al, 2009) (http://www.proteinatlas.org/search/PHPT1). In addition, proteins with homology to the PHPT1 protein can be found in most animals, but is lacking in bacteria, plant or fungi (Ma et al, 2005;Klumpp et al, 2010;Besant and Attwood, 2012).…”

Section: Introductionmentioning

confidence: 99%

A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome

Inturi

Wäneskog

Vlachakis

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Regulation of protein activity by phosphorylation is central in many cellular processes. Phosphorylation of serine, threonine and tyrosine residues is well documented and studied. In addition, other amino acids, like histidine can be phosphorylated, but neither the mechanism nor the function of this modification is well understood. Nevertheless, there is a 14 kDa enzyme with phosphohistidine phosphatase activity, named PHPT1, found in most animals, but not in bacteria, plant or fungi. There are a few splice variant transcripts formed from the human PHPT1 locus and some of them are predicted to form variant proteins, but studies of these proteins are lacking. In order to get insight into the possible function of the variant transcripts encoded at the PHPT1 locus, ectopic expression of PHPT1 transcript variant 6, predicted to be degraded by the non-sense mediated mRNA decay pathway, in HeLa cells was undertaken. In HeLa cells the splice variant protein was degraded by the proteasome, unlike the wild type protein. Using an in silico modeling approach the variant C-terminal end of the proteins were predicted to form different secondary structures that might explain the different properties of the two proteins. The specific degradation of the PHPT1 splice variant indicates that at least for the PHPT1 protein, the quality control and the self-guarding of the cellular system works at two levels, first at the RNA level, aberrant transcripts are degraded by the non-sense mediated mRNA decay pathway, and the small amount of proteins that are formed will be degraded by the proteasome.

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Section: Introductionmentioning

confidence: 99%

A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome

Inturi

Wäneskog

Vlachakis

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…These studies also determined inhibitory constants for various known inhibitors of phosphatases (e.g., inhibitors 1 and 2, okadaic acid, and mictocystin-LR) against p-His dephosphorylation using phosphorylated histone 4 as the substrate. Furthermore, immunohistochemical studies by Zhang et al (45) have suggested expression of PHP in several mouse and human tissues. Our current findings provide the evidence for expression of PHP in insulin-secreting INS 832/13 cells, normal rat islets, and human islets.…”

Section: Php Expression Is Increased In ␤-Cells Under In Vitro Conditmentioning

confidence: 99%

Regulation of glucose- and mitochondrial fuel-induced insulin secretion by a cytosolic protein histidine phosphatase in pancreatic β-cells

Kamath

Kyathanahalli

Jayaram

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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localization of a cytosolic protein histidine phosphatase (PHP; ϳ16 kDa) in INS 832/13 cells, normal rat islets, and human islets. siRNA-mediated knockdown of PHP markedly reduced glucose-or mitochondrial fuel-induced but not KCl-induced insulin secretion. siRNA-mediated knockdown of PHP also attenuated mastoparan-induced insulin secretion, suggesting its participation in G protein-sensitive signaling steps, leading to insulin secretion. Functional assays revealed that the ␤-cell PHP catalyzes the dephosphorylation of ATP-citrate lyase (ACL). Silencing of PHP expression markedly reduced ACL activity, suggesting functional regulation of ACL by PHP in ␤-cells. Coimmunoprecipitation studies revealed modest effects of glucose on the interaction between PHP and ACL. Confocal microscopic evidence indicated that glucose promotes association between ACL and nm23-H1, a known kinase histidine kinase, but not between PHP and ACL. Furthermore, metabolic viability of INS 832/13 cells was resistant to siRNA-PHP, suggesting no regulatory roles of PHP in cell viability. Finally, long-term exposure (24 h) of INS 832/13 cells or rat islets to high glucose (30 mM) increased the expression of PHP. Such increases in PHP expression were also seen in islets derived from the Zucker diabetic fatty rat compared with islets from the lean control animals. Together, these data implicate regulatory roles for PHP in a G protein-sensitive step involved in nutrient-induced insulin secretion. In light of the current debate on putative regulatory roles of ACL in insulin secretion, additional studies are needed to precisely identify the phosphoprotein substrate(s) for PHP in the cascade of events leading to nutrient-induced insulin secretion. nm23-H1; adenosine 5=-triphosphate-citrate lyase IT IS WELL ESTABLISHED THAT in the majority of cell types transduction of extracellular signals involves ligand binding to a receptor, often followed by the activation of one or more GTP-binding proteins (G proteins) and their effector systems (7). The pancreatic ␤-cell is unusual in that glucose, the major physiological agonist, lacks an extracellular receptor. Instead, events consequent to glucose metabolism promote insulin secretion via the generation and/or altered distribution of diffusible second messengers such as calcium, cAMP, and lipid hydrolytic products of various phospholipases (5,28,32,34,36). It is noteworthy that a selective increase in intracellular calcium not only initiates insulin secretion but also regulates various enzymes such as protein kinases, phosphodiesterases, adenylyl cyclases, and phospholipases, thereby facilitating insulin secretion. In the context of protein kinases, in addition to calcium-dependent protein kinase(s), several other kinases, including calmodulin-, cyclic nucleotide-, and phospholipiddependent protein kinases, tyrosine kinases, and mitogen-

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“…8,14,15 Phosphohistidine is widely used in signal transduction activity of the eukaryotic cells, and accounts for 6% of the protein-bound phosphate. 16 The function of phosphohistidine in eukaryotes is little studied, however, compared with serine/ threonine and tyrosine phosphorylation. Analysis of the molecular structure of phosphohistidine has shown that the phosphoramidate bond in phosphohistidine at the 1-N and 3-N positions of the imidazole ring is different from the phosphoester bond in phosphohydroxyamino acids.…”

Section: Introductionmentioning

confidence: 99%

“…16 In the National Center for Biotechnology Information UniGene database, 31 mRNA levels of PHPT1 are shown to be high in the mammary gland, heart, pituitary gland and parathyroid glands, suggesting that PHPT1 might have a role in cell proliferation and differentiation.…”

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Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma

et al. 2015

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Objective: To explore expression and clinical relevance of phosphohistidine phosphatase 1 (PHPT1) in clear-cell renal cell carcinoma. Methods: Patients with clear-cell renal cell carcinoma who underwent radical or nephron-sparing nephrectomy were enrolled. Correlations between PHPT1 expression and demographic and clinical characteristics were analysed prospectively. Results: In total, 122 patients (78 male/44 female) were included. In normal kidney tissue, PHPT1 expression was observed only in the proximal tubule. High PHPT1 expression levels were associated with larger tumour size, higher Fuhrman nuclear grade and advanced pathological tumour-node-metastasis (pTNM) stage compared with low PHPT1 expression levels. Patients with low PHPT1 expression showed better overall survival and progression-free survival compared with those with high PHPT1 expression. In addition, multivariate analysis showed that nuclear grade and pTNM stage were independent predictors of progression-free survival and overall survival in patients with clear-cell renal cell carcinoma. PHPT1 expression was also an independent predictor of overall survival but not progression-free survival. Conclusions: PHPT1 was expressed in the epithelium of proximal tubuli and nuclei of clear-cell renal cell carcinoma tissue samples. High levels of 14 kDa phosphohistidine phosphatase protein were negatively associated with overall survival and progression-free survival in patients with clear-cell renal cell carcinoma.

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Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues

Cited by 14 publications

References 13 publications

A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome

A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome

Regulation of glucose- and mitochondrial fuel-induced insulin secretion by a cytosolic protein histidine phosphatase in pancreatic β-cells

Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma

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