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HORMONES AND SIGNALING

CRHSP-24 phosphorylation is regulated by multiple signaling pathways in pancreatic acinar cells

¹Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; and ²Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706

Submitted 11 March 2003 ; accepted in final form 3 June 2003

Ca²⁺-regulated heat-stable protein of 24 kDa (CRHSP-24) is a serine phosphoprotein originally identified as a physiological substrate for the Ca²⁺-calmodulin regulated protein phosphatase calcineurin (PP2B). CRHSP-24 is a paralog of the brain-specific mRNA-binding protein PIPPin and was recently shown to interact with the STYX/dead phosphatase protein in developing spermatids (Wishart MJ and Dixon JE. Proc Natl Acad Sci USA 99: 2112–2117, 2002). Investigation of the effects of phorbol ester (12-o-tetradecanoylphorbol-13-acetate; TPA) and cAMP analogs in ³²P-labeled pancreatic acini revealed that these agents acutely dephosphorylated CRHSP-24 by a Ca²⁺-independent mechanism. Indeed, cAMP- and TPA-mediated dephosphorylation of CRHSP-24 was fully inhibited by the PP1/PP2A inhibitor calyculin A, indicating that the protein is regulated by an additional phosphatase other than PP2B. Supporting this, CRHSP-24 dephosphorylation in response to the Ca²⁺-mobilizing hormone cholecystokinin was differentially inhibited by calyculin A and the PP2B-selective inhibitor cyclosporin A. Stimulation of acini with secretin, a secretagogue that signals through the cAMP pathway in acini, induced CRHSP-24 dephosphorylation in a concentration-dependent manner. Isoelectric focusing and immunoblotting indicated that elevated cellular Ca²⁺ dephosphorylated CRHSP-24 on at least three serine sites, whereas cAMP and TPA partially dephosphorylated the protein on at least two sites. The cAMP-mediated dephosphorylation of CRHSP-24 was inhibited by low concentrations of okadaic acid (10 nM) and fostriecin (1 µM), suggesting that CRHSP-24 is regulated by PP2A or PP4. Collectively, these data indicate that CRHSP-24 is regulated by diverse and physiologically relevant signaling pathways in acinar cells, including Ca²⁺, cAMP, and diacylglycerol.

exocrine pancreas; protein phosphatase; cyclic adenosine 5'-monophosphate; secretin; cholecystokinin; Ca²⁺-regulated heat-stable protein of 24 kDa

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