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Emerging roles for protein histidine phosphorylation in cellular signal transduction: lessons from the islet β-cell

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      Protein phosphorylation represents one of the key regulatory events in physiological insulin secretion from the islet β-cell. In this context, several classes of protein kinases ( e.g. calcium-, cyclic nucleotide- and phospholipid-dependent protein kinases and tyrosine kinases) have been characterized in the β-cell. The majority of phosphorylated amino acids identified include phosphoserine, phosphothreonine and phosphotyrosine. Protein histidine phosphorylation has been implicated in the prokaryotic and eukaryotic cellular signal transduction. Most notably, phoshohistidine accounts for 6% of total protein phosphorylation in eukaryotes, which makes it nearly 100-fold more abundant than phosphotyrosine, but less abundant than phosphoserine and phosphothreonine. However, very little is known about the number of proteins with phosphohistidines, since they are highly labile and are rapidly lost during phosphoamino acid identification under standard experimental conditions. The overall objectives of this review are to: ( i) summarize the existing evidence indicating the subcellular distribution and characterization of various histidine kinases in the islet β-cell, ( ii) describe evidence for functional regulation of these kinases by agonists of insulin secretion, ( iii) present a working model to implicate novel regulatory roles for histidine kinases in the receptor-independent activation, by glucose, of G-proteins endogenous to the β-cell, ( iv) summarize evidence supporting the localization of protein histidine phosphatases in the islet β-cell and ( v) highlight experimental evidence suggesting potential defects in the histidine kinase signalling cascade in islets derived from the Goto-Kakizaki (GK) rat, a model for type 2 diabetes. Potential avenues for future research to further decipher regulatory roles for protein histidine phosphorylation in physiological insulin secretion are also discussed.

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            Author and article information

            [a ]Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University Detroit, MI, USA
            [b ]β-Cell Biochemistry Research Laboratory, John D Dingell VA Medical Center Detroit, MI, USA
            Author notes
            * Correspondence to: Anjan KOWLURU, Ph.D., Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA. Tel.: 313–576-4478 Fax: 313–576-1112 E-mail: akowluru@
            J Cell Mol Med
            J. Cell. Mol. Med
            Journal of Cellular and Molecular Medicine
            John Wiley & Sons, Ltd (Chichester, UK )
            October 2008
            08 April 2008
            : 12
            : 5b
            : 1885-1908
            18400053 4506158 10.1111/j.1582-4934.2008.00330.x
            © 2008 The Author Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd


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