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Review
, 40, 1-9

Protein Kinase C Isoforms in the Normal Pancreas and in Pancreatic Disease

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Review

Protein Kinase C Isoforms in the Normal Pancreas and in Pancreatic Disease

Alicia K Fleming et al. Cell Signal.

Abstract

Protein Kinase C isoforms have been implicated in regulating multiple processes within the healthy pancreas. Moreover, their dysregulation contributes to all aspects of pancreatic disease. In this review, with a focus on acinar, ductal, and islet cells, we highlight the roles and contributions of the different PKC isoforms to normal pancreas function. We also discuss the contribution of PKC enzymes to pancreatic diseases, including insulin resistance and diabetes mellitus, as well as pancreatitis and the development and progression of pancreatic cancer.

Keywords: PKC; Pancreas; Pancreatic cancer; Pancreatitis; Protein kinase C.

Figures

Figure 1
Figure 1
PKC structure is similar across family members, although they have different activation requirements. The inhibitory pseudosubstrate domain and the kinase domain, consisting of C3 and C4, are similar amongst PKCs, but the regulatory domains differ. Conventional PKCs (cPKCs) require DAG and calcium binding, while novel PKCs (nPKCs) require DAG binding, and atypical PKCs (aPKCs) require neither DAG nor calcium binding, although they have a single Cys-rich motif (C1).
Figure 2
Figure 2
PKC functions in the normal pancreas. PKCs regulate hormone secretion in the islets, amylase secretion in acinar cells, and bicarbonate secretion in ductal cells of normal pancreatic tissue. In islets, PKCα and PKCδ regulate Glucagon secretion from alpha-cells. In addition PKCs regulate insulin secretion in beta-cells. Amylase secretion is increased in acinar cells after stimulation of the CCK receptor and bicarbonate secretion is downregulated in ductal cells after activation of PKC via Substance P.
Figure 3
Figure 3
Roles of PKC isoforms in islet function. In diabetes mellitus development, PKCζ activity promotes beta cell proliferation through mTOR activation, while PKCδ promotes dysfunction and destruction of beta cells via iNOS expression and TLR2 signaling. In a type two diabetes model where islets are pre-treated with fatty acids, PKCε is integral to the resulting decrease in insulin secretion.
Figure 4
Figure 4
Schematic of how PKD isoforms contribute to pancreatic inflammation (pancreatitis). PKCα can aid basolateral exocytosis via phosphorylation of Munc18c. This leads to Munc18c degradation and release of Syntaxin-4 and formation of the SNARE complex. PKCε has been implicated in necrosis linked to pancreatitis and both, PKCδ, and PKCε also contribute to trypsinogen activation and activation of NF-κB, which drives inflammation.
Figure 5
Figure 5
Schematic of a progression model for pancreatic cancer. Current belief is that acinar cells (acini) can undergo acinar-to-ductal metaplasia (ADM). In presence of an oncogenic KRAS mutation, ADM lesions further develop into pancreatic intraepithelial neoplasia (PanIN), which then can progress to pancreatic cancer. PKCδ and PKCι contribute to the early event of ADM and additional PKCs mediate the growth and progression of pancreatic cancer by aiding angiogenesis, proliferation, anchorage-independent growth, and metastasis, while also preventing radiosensitization.

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