Role of serine/threonine phosphatases 1 and 2A in pancreatic acinar fluid and electrolyte secretion

Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation, and secretion. However, their roles in various pancreatic exocrine functions, such as pancreatic acinar fluid/electrolyte secretion, is still unclear. Therefore, in the present study, we examined the ability of vasoactive intestinal peptide (VIP) and secretin, which stimulate cAMP generation in pancreatic acini, to activate serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A), the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na⁺-K⁺-ATPase). Our results demonstrate that VIP and secretin activate PP1 and PP2A. However, they differ in their signaling cascades. Both VIP and secretin stimulate PP1 through cAMP-stimulated activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). However, VIP stimulates PP2A through the activation of cAMP-mediated EPAC, whereas secretin does it through activation of PKA. Despite these differences, in cAMP effect on activation, both VIP and secretin activate PP2A through a p21-activated kinase 4 (PAK4)-mediated mechanism, without involvement of PAK2. Furthermore, PP1 and PP2A activation is needed for Na⁺-K⁺-ATPase activation, which mediates pancreatic acinar fluid and electrolyte secretion. These results support the conclusion that PP1 and PP2A play an important role in pancreatic acinar fluid and electrolyte secretion, mediated by a PAK4-dependent mechanism, which when combined with their recently described roles in pancreatic enzyme secretion, pancreatitis, and pancreatic acinar growth and cancer, demonstrate the important roles they play in both physiological and pathological responses in the exocrine pancreas, similar to their previously established roles in the endocrine pancreas.<b>NEW & NOTEWORTHY</b> The roles of the serine/threonine phosphatase 1/2A in mediating fluid/electrolyte secretion by pancreatic acinar cells remains unclear. This study demonstrates that PP1/PP2A are activated vasoactive intestinal peptide (VIP)/secretin in pancreatic acini. VIP/secretin both activate PP1/PP2A but differed for their ability to activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA). VIP/secretin require PAK4, not PAK2, activation to stimulate PP2A, not PP1; however, PP1/PP2A activation stimulate sodium-potassium adenosine triphosphatase (Na⁺-K⁺-ATPase) activity. This study shows that PP1/PP2A play important roles in VIP-secretin-stimulated pancreatic acinar fluid/electrolyte secretion.