QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 5, 2339-2347, May 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E07-11-1130v1 19/5/2339    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Singh, V. P. Articles by McNiven, M. A. PubMed PubMed Citation Articles by Singh, V. P. Articles by McNiven, M. A.

Src-mediated Cortactin Phosphorylation Regulates Actin Localization and Injurious Blebbing in Acinar Cells

Department of Biochemistry and Molecular Biology and the Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN 55905

Submitted November 12, 2007; Revised February 8, 2008; Accepted March 3, 2008
Monitoring Editor: Josephine Adams

Suprastimulation of pancreatic acini is a well-known model for pancreatitis, and it is characterized by actin reorganization and cell blebbing. Currently, however, the mechanisms underlying regulation of these aberrant cytoskeletal and membrane dynamics and how they contribute to cell injury are unclear. We observed that suprastimulation results in a rapid activation of Src and relocalization of the actin-binding protein cortactin from the apical to the basolateral domain at the necks of membrane blebs. Furthermore, Src-mediated cortactin tyrosine phosphorylation was markedly increased after suprastimulation. Pretreatment of acini with Src inhibitors or expression of a cortactin tyrosine phospho-inhibitory mutant reduced actin redistribution and bleb formation induced by suprastimulation in vitro. Importantly, inhibition of Src activity in rat models of suprastimulation-induced pancreatitis substantially reduced disease severity, as indicated by a reduction in serum amylase and pancreatic edema and a striking improvement in tissue histology. These findings indicate a novel, disease-relevant role for Src-mediated cortactin phosphorylation in aberrant reorganization of the actin cytoskeleton, a mechanism that is likely to have implications in other types of cell injury. In addition, they suggest a potential use for Src inhibitors as an approach to reduce cell injury.

Address correspondence to: Mark A. McNiven (mcniven.mark{at}mayo.edu)

Abbreviations used: CCK, cholecystokinin; CER, caerulein; M3 cortactin, a cortactin tyrosine phospho-mutant in which three key tyrosine residues have been mutated to phenylalanine; SS, suprastimulation; WT, wild type.

This article has been cited by other articles:

				O. T. Fackler and R. Grosse Cell motility through plasma membrane blebbing J. Cell Biol., June 16, 2008; 181(6): 879 - 884. [Abstract] [Full Text] [PDF]