TY - JOUR
T1 - Effects of second messengers on serine/threonine protein phosphatases in insulin-secreting cells
AU - Sjöholm, Åke
AU - Berggren, Per Olof
AU - Honkanen, Richard E.
N1 - Funding Information:
Financial support was received from the Swedish Medical Research Council (No. 72X-12550, 72X-00034, 72X-09890, 72XS-12708), the Cancer Foundation, SmithKline Beecham Pharma AB, the Wenner-Gren Foundation, Funds of Karolinska Institutet, Sven-ska Diabetesstiftelsen, Swedish Match, the Swedish Diabetes Association, the Swedish Society of Medicine, Åke Wiberg’s Foundation, Magn. Bergvall’s Fund, the Nordic Insulin Foundation, the Novo Nordisk Insulin Foundation Committee, the Novo Nordisk Foundation, Fredrik and Inger Thuring’s Foundation, Torsten and Ragnar Söderberg’s Foundations, Novo-Nordisk Sweden Pharma AB, Harald Jeansson’s and Harald, and Greta Jeansson’s Foundations, Tore Nilsson’s Foundation for Medical Research, Berth von Kantzow’s Foundation, Barndiabetesfonden and Syskonen Svensson’s Fund, and an Intramural grant from the College of Medicine, University of South Alabama, and NIH CA 60750 (to R.E.H.).
PY - 2001
Y1 - 2001
N2 - Reversible protein phosphorylation is an important and versatile mechanism by which cells transduce external signals into biological responses. Cellular levels of protein phosphorylation are determined by the balanced actions of both protein kinases and protein phosphatases (PPases). Compared with protein kinases, however, serine/threonine PPases have received less attention. In the present study, the effects of certain insulin secretagogues and intracellular second messengers, known to stimulate or inhibit insulin secretion, on the activities of cation-independent serine/threonine PPases were investigated in insulin-secreting RINm5F insulinoma cells. Raising cellular cAMP through adenylyl cyclase activation and phosphodiesterase inhibition in intact cells, evoked inhibitory effects on PPase activities. The addition of a nitric oxide donor, cyclic nucleotides, or proinflammatory prostaglandins to RINm5F cell homogenates at widely different concentrations did not affect type-1 or -2A PPase activities. Phosphatidyl serine seemingly activated PPase-1, while inactivating PPase-2A. A protein kinase C-activating phorbol ester produced the opposite results when added to RINm5F cell homogenates. These studies suggest that several known intracellular second messengers are without effect on β-cell PPase activities. However, phosphatidyl serine and protein kinase C activation, whose activity is transiently increased by glucose, may promote insulin release through PPase inactivation, likely contributing to the increase in phosphorylation state that occurs after stimulation of insulin release. Thus, inhibition of protein dephosphorylation may be a novel regulatory mechanism, assisting in activation of the stimulus-secretion coupling in insulin-producing cells.
AB - Reversible protein phosphorylation is an important and versatile mechanism by which cells transduce external signals into biological responses. Cellular levels of protein phosphorylation are determined by the balanced actions of both protein kinases and protein phosphatases (PPases). Compared with protein kinases, however, serine/threonine PPases have received less attention. In the present study, the effects of certain insulin secretagogues and intracellular second messengers, known to stimulate or inhibit insulin secretion, on the activities of cation-independent serine/threonine PPases were investigated in insulin-secreting RINm5F insulinoma cells. Raising cellular cAMP through adenylyl cyclase activation and phosphodiesterase inhibition in intact cells, evoked inhibitory effects on PPase activities. The addition of a nitric oxide donor, cyclic nucleotides, or proinflammatory prostaglandins to RINm5F cell homogenates at widely different concentrations did not affect type-1 or -2A PPase activities. Phosphatidyl serine seemingly activated PPase-1, while inactivating PPase-2A. A protein kinase C-activating phorbol ester produced the opposite results when added to RINm5F cell homogenates. These studies suggest that several known intracellular second messengers are without effect on β-cell PPase activities. However, phosphatidyl serine and protein kinase C activation, whose activity is transiently increased by glucose, may promote insulin release through PPase inactivation, likely contributing to the increase in phosphorylation state that occurs after stimulation of insulin release. Thus, inhibition of protein dephosphorylation may be a novel regulatory mechanism, assisting in activation of the stimulus-secretion coupling in insulin-producing cells.
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U2 - 10.1006/bbrc.2001.4789
DO - 10.1006/bbrc.2001.4789
M3 - Article
C2 - 11327709
AN - SCOPUS:0034810151
VL - 283
SP - 364
EP - 368
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -