HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 13, 9536-9546, March 30, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/13/9536    most recent M610553200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Z. Articles by Thurmond, D. C. Search for Related Content PubMed PubMed Citation Articles by Wang, Z. Articles by Thurmond, D. C. Social Bookmarking                      What's this?

Glucose-stimulated Cdc42 Signaling Is Essential for the Second Phase of Insulin Secretion^*

From the Department of Biochemistry and Molecular Biology and Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202

The small Rho family GTPases Cdc42 and Rac1 have each been shown to function in insulin exocytosis and are presumed to function in actin remodeling and insulin granule mobilization. However, whether either GTPase is required for the mobilization phase of insulin release (second phase) and are linked in a common signaling pathway has remained unknown. Here we demonstrate that small interfering RNA-mediated depletion of Cdc42 from isolated islets results in the selective loss of secondphase insulin release. Consistent with a role in this nutrient-dependent phase, Cdc42 activation was detected exclusively in response to D-glucose and was unresponsive to KCl or non-metabolizable glucose analogs in MIN6 -cells. Cdc42 activation occurred early in secretion (3 min), whereas Rac1 activation required 15–20 min, suggesting Cdc42 as proximal and Rac1 as distal regulators of second-phase secretion. Importantly, Rac1 activation and function was linked in a common pathway downstream of Cdc42; Cdc42 depletion ablated glucose-induced Rac1 activation, and expression of constitutively active Rac1 in Cdc42-depleted cells functionally restored glucose-stimulated insulin secretion. Occurring at a time midway between Cdc42 and Rac1 activations was the phosphorylation of p21-activated-kinase 1 (Pak1), and this phosphorylation event required Cdc42. Moreover, small interfering RNA-mediated Pak1 depletion abolished Rac1 activation and glucose-stimulated insulin release, suggesting that Pak1 may mediate the link between Cdc42 and Rac1 in this pathway. Taken together, these data substantiate the existence of a novel signaling pathway in the islet -cell whereby Cdc42 functions as a key proximal transmitter of the glucose signal early in stimulus-secretion coupling to support the later stage of insulin release.

Received for publication, November 13, 2006 , and in revised form, February 2, 2007.

^* This study was supported by American Diabetes Association Grant 1-03-CD-10 and National Institutes of Health Grant DK-067912 (to D. C. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 635 Barnhill Dr., MS4053, Indianapolis, IN 46202. Tel.: 317-274-1551; Fax: 317-274-4686; E-mail: dthurmon{at}iupui.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. G. Pedersen and A. Sherman Newcomer insulin secretory granules as a highly calcium-sensitive pool PNAS, May 5, 2009; 106(18): 7432 - 7436. [Abstract] [Full Text] [PDF]

				E. Hammar, A. Tomas, D. Bosco, and P. A. Halban Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic {beta}-Cell Function Endocrinology, May 1, 2009; 150(5): 2072 - 2079. [Abstract] [Full Text] [PDF]

				Z. Wang and D. C. Thurmond Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins J. Cell Sci., April 1, 2009; 122(7): 893 - 903. [Abstract] [Full Text] [PDF]

				M. G. Pedersen, A. Corradin, G. M Toffolo, and C. Cobelli A subcellular model of glucose-stimulated pancreatic insulin secretion Phil Trans R Soc A, October 13, 2008; 366(1880): 3525 - 3543. [Abstract] [Full Text] [PDF]

				E. Ispanovic, D. Serio, and T. L. Haas Cdc42 and RhoA have opposing roles in regulating membrane type 1-matrix metalloproteinase localization and matrix metalloproteinase-2 activation Am J Physiol Cell Physiol, September 1, 2008; 295(3): C600 - C610. [Abstract] [Full Text] [PDF]

				J. L. Jewell, E. Oh, S. M. Bennett, S. O. Meroueh, and D. C. Thurmond The Tyrosine Phosphorylation of Munc18c Induces a Switch in Binding Specificity from Syntaxin 4 to Doc2{beta} J. Biol. Chem., August 1, 2008; 283(31): 21734 - 21746. [Abstract] [Full Text] [PDF]

				J. L. Jewell, W. Luo, E. Oh, Z. Wang, and D. C. Thurmond Filamentous Actin Regulates Insulin Exocytosis through Direct Interaction with Syntaxin 4 J. Biol. Chem., April 18, 2008; 283(16): 10716 - 10726. [Abstract] [Full Text] [PDF]