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

J. Biol. Chem., Vol. 280, Issue 40, 33847-33855, October 7, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/40/33847    most recent M501718200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chattopadhyay, S. Articles by Sen, I. Search for Related Content PubMed PubMed Citation Articles by Chattopadhyay, S. Articles by Sen, I. Social Bookmarking                      What's this?

Calmodulin Binds to the Cytoplasmic Domain of Angiotensin-converting Enzyme and Regulates Its Phosphorylation and Cleavage Secretion^*

Saurabh Chattopadhyay, Kizhakkekara R. Santhamma, Saubhik Sengupta1, Brian McCue, Michael Kinter¶, Ganes C. Sen, and Indira Sen2

From the Departments of Molecular Cardiology, Molecular Genetics, and ^¶Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

The rate of cleavage secretion of the enzymatically active ectodomain of angiotensin-converting enzyme (ACE) is regulated by tyrosine phosphorylation of the protein and by the phorbol ester, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Here, we report that both calmodulin inhibitor (CaMI) and calmodulin kinase inhibitor could also enhance cleavage secretion of ACE. This effect was accompanied by the dissociation of calmodulin from a specific region within the cytoplasmic domain of ACE to which it had been bound. The same domain of ACE was phosphorylated, and both CaMI and PMA caused dephosphorylation of ACE as well. Mass spectrometric and mutational analyses identified Ser⁷³⁰ as the only phosphorylated residue in the cytoplasmic domain of ACE. The Ser⁷³⁰ Ala mutant of ACE was not phosphorylated, but it still bound calmodulin, and its cleavage secretion was enhanced by both CaMI and PMA. Similarly, when Ser⁷³⁰ was replaced by the phosphoserine mimetic, Asp, cleavage secretion of the resultant mutant remained susceptible to the enhancing effect of CaMI and PMA. These results demonstrate that, although CaMI and PMA can enhance both cleavage secretion of ACE and its dephosphorylation, the two effects are not mutually interdependent.

Received for publication, February 15, 2005 , and in revised form, July 21, 2005.

^* This work was supported by the National Institutes of Health Grants HL54297 (to I. S.) and HL48258 (to G. C. S.). 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 Present address: Dept. of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

² To whom correspondence should be addressed: Dept. of Molecular Cardiology/NB50, The Cleveland Clinic Foundation, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195. Tel.: 216-444-9057; Fax: 216-444-9263; E-mail: seni{at}ccf.org.

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

This article has been cited by other articles:

				E. E. Gardiner, D. Karunakaran, J. F. Arthur, F.-T. Mu, M. S. Powell, R. I. Baker, P. M. Hogarth, M. L. Kahn, R. K. Andrews, and M. C. Berndt Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing Fc{gamma}RIIa Blood, January 1, 2008; 111(1): 165 - 174. [Abstract] [Full Text] [PDF]

				C. Kojima, A. Kawakami, T. Takei, K. Nitta, and M. Yoshida Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 855 - 860. [Abstract] [Full Text] [PDF]

				I. Fleming Signaling by the Angiotensin-Converting Enzyme Circ. Res., April 14, 2006; 98(7): 887 - 896. [Abstract] [Full Text] [PDF]