Membrane Biology and Protein Trafficking in Digestive Epithelia
The exocrine pancreas is responsible for the synthesis, storage and secretion of digestive enzymes that are necessary for the breakdown and assimilation of the diet. This process occurs within the functional unit of the gland known as the acinus. Hormones and neurotransmitters act on G-protein coupled receptors located on the plasma membrane, setting in motion a series of biochemical signals culminating in the exocytosis of digestive enzymes into the pancreatic duct. The main intracellular messenger mediating exocytosis is a rise in the concentration of cellular Ca2+. Under pathophysiological conditions aberrant elevations in Ca2+ both inhibit exocytosis and promote a lysosome-mediated activation of digestive enzymes marking the earliest stages of pancreatitis. In spite of substantial advances made in understanding the mechanism(s) mediating Ca2+ mobilization, comparatively less is known of the regulatory proteins that respond to elevated Ca2+ in the cytoplasm. The major focus of this laboratory is to elucidate the precise down-stream molecular events that occur as a consequence of acutely elevated Ca2+ in secretory epithelia. Elucidation of Ca2+-signaling pathways in pancreas is essential to understand the pathophysiology of acute pancreatitis and pancreatic cancer.
Lugea A, Waldron RT, Mareninova OA, Shalbueva N, Deng N, Su HY, Thomas DT, Jones EK, Messenger SW, Yang J, Hu C, Gukovsky I, Liu X, Groblewski GE, Gukovskaya AS, Gorelick FS, Pandol SJ. Human pancreatic acinar cells: proteomic characterization, physiologic responses, and organellar disorders in ex vivo pancreatitis. Am J Path. 187:2726-2743, Epub Sept 2017
Messenger SW, Jones EK, Holthaus CL, Thomas DD, Cooley MM, Byrne JA, Mareniniova OA, Gukovskaya, Groblewski GE. Acute Acinar Pancreatitis Blocks VAMP8-Dependent Secretion Resulting in Intracellular Trypsin Accumulation. J Biol Chem. 292:7828-7839, Epub Feb 2017
Messenger SW, Thomas DD, Cooley M, Jones EK, Falkowski MA, Fernandez LS, Gorelick, FS, Groblewski GE. Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells. Cell and Mol Gastro and Hep. Accepted for Publication September 2015.
Messenger SW, Falkowski MA, Thomas DD, Jones EK, Hong W, Gaisano HY, Boulis NM, Groblewski GE. Vesicle Associated Membrane Protein 8 (VAMP8) Mediated Zymogen Granule Exocytosis is Dependent on Endosomal Trafficking via the Constitutive-Like Secretory Pathway. J Biol Chem. 289:28040-28053. Epub Aug. 2014
Messenger SW, Falkowski MA, Groblewski GE. Mechanisms of Ca2+-dependent secretion in pancreatic and parotid acinar cells. Cell Calcium. 55:369-375. Epub 2014.
Messenger SW, Thomas DD, Falkowski MA, Byrne JA, Gorelick FS, Groblewski GE. Tumor Protein D52 Controls Trafficking of an Apical Endolysosomal Secretory Pathway in Pancreatic Acinar Cells. Am J Physiol. 305:G439-452 Epub June 2013.