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J. Biol. Chem., Vol. 281, Issue 38, 28450-28459, September 22, 2006

This Article Full Text Full Text (PDF) Supplemental Data An addition or correction has been published All Versions of this Article: 281/38/28450    most recent M606054200v1 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 Erdogan, E. Articles by Fields, A. P. Search for Related Content PubMed PubMed Citation Articles by Erdogan, E. Articles by Fields, A. P. Social Bookmarking                      What's this?

Aurothiomalate Inhibits Transformed Growth by Targeting the PB1 Domain of Protein Kinase C^*

Eda Erdogan, Trond Lamark, Melody Stallings-Mann, Lee Jamieson, Mauricio Pellechia^¶, E. Aubrey Thompson, Terje Johansen, and Alan P. Fields¹

From the Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, the Department of Biochemistry, Institute of Medical Biology, University of Tromsoe, 9037 Tromsoe, Norway, and ^¶The Burnham Institute, La Jolla, California 92037

We recently identified the gold compound aurothiomalate (ATM) as a potent inhibitor of the Phox and Bem1p (PB1)-PB1 domain interaction between protein kinase C (PKC) and the adaptor molecule Par6. ATM also blocks oncogenic PKC signaling and the transformed growth of human lung cancer cells. Here we demonstrate that ATM is a highly selective inhibitor of PB1-PB1 domain interactions between PKC and the two adaptors Par6 and p62. ATM has no appreciable inhibitory effect on other PB1-PB1 domain interactions, including p62-p62, p62-NBR1, and MEKK3-MEK5 interactions. ATM can form thio-gold adducts with cysteine residues on target proteins. Interestingly, PKC (and PKC) contains a unique cysteine residue, Cys-69, within its PB1 domain that is not present in other PB1 domain containing proteins. Cys-69 resides within the OPR, PC, and AID motif of PKC at the binding interface between PKC and Par6 where it interacts with Arg-28 on Par6. Molecular modeling predicts formation of a cysteinyl-aurothiomalate adduct at Cys-69 that protrudes into the binding cleft normally occupied by Par6, providing a plausible structural explanation for ATM inhibition. Mutation of Cys-69 of PKC to isoleucine or valine, residues frequently found at this position in other PB1 domains, has little or no effect on the affinity of PKC for Par6 but confers resistance to ATM-mediated inhibition of Par6 binding. Expression of the PKC C69I mutant in human non-small cell lung cancer cells confers resistance to the inhibitory effects of ATM on transformed growth. We conclude that ATM inhibits cellular transformation by selectively targeting Cys-69 within the PB1 domain of PKC.

Received for publication, June 23, 2006 , and in revised form, July 18, 2006.

^* This work was supported in part by Grant LCD-22766-N from the American Lung Association and grants from the Mayo Foundation (to A. P. F.) and from the Norwegian Cancer Society and the Norwegian Research Council (to T. J.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table I.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology, Mayo Clinic College of Medicine, 4500 San Pablo Rd., Griffin Cancer Research Bldg., 312, Jacksonville, FL 32224. Tel.: 904-953-6109; Fax: 904-953-0277; E-mail: fields.alan{at}mayo.edu.

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				R. P. Regala, E. A. Thompson, and A. P. Fields Atypical Protein Kinase C{iota} Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells Cancer Res., July 15, 2008; 68(14): 5888 - 5895. [Abstract] [Full Text] [PDF]