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12/13 IN NIH3T3 CELLS
1 Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: jawillms{at}umich.edu.
Cholecystokinin (CCK) is a major regulator of pancreatic acinar cells and has been shown previously to be capable of inducing cytoskeletal changes in these cells. In the present study, using NIH3T3 cells stably transfected with CCKA receptors as a model cell, we demonstrate that CCK can induce actin stress fibers through a G13 and RhoA dependent mechanism. CCK induced stress fibers within minutes similar to those induced by lysophosphatidic acid (LPA), the active component of serum. The effects of CCK were mimicked by active RhoV14 and blocked by dominant negative RhoN19, C. botulinum C3 transferase, and the Rho-kinase inhibitor, Y27632. CCK rapidly induced active Rho in cells as shown with a pull down assay using the Rho binding domain of rhotekin and by a SRE-luciferase reporter assay. To evaluate the G protein mediating the action of CCK, cells were transfected with active alpha subunits; G
13 and G12 but not Gq induced stress fibers and in some cases cell rounding. A p115 RhoGEF RGS domain known to interact with G12/13 inhibited active 12/13 and CCK induced stress fibers while RGS2 and RGS4 which are known to inhibit Gq had no effect. Cotransfection with plasmids coding for the G protein subunit C terminal peptide from 13 and to a lesser extent 12 also inhibited the effect of CCK, while the peptide from q did not. These results show that in NIH3T3 cells bearing CCKA receptors, CCK activates Rho primarily through G13 leading to rearrangement of the actin cytoskeleton.
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