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Originally published In Press as doi:10.1074/jbc.M505402200 on July 1, 2005

J. Biol. Chem., Vol. 280, Issue 35, 31109-31115, September 2, 2005
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Atypical Protein Kinase C{iota} Plays a Critical Role in Human Lung Cancer Cell Growth and Tumorigenicity*

Roderick P. Regala, Capella Weems, Lee Jamieson, John A. Copland, E. Aubrey Thompson, and Alan P. Fields{ddagger}

From the Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224

Atypical protein kinase C (aPKC) isozymes function in epithelial cell polarity, proliferation, and survival and have been implicated in cellular transformation. However, the role of these enzymes in human cancer is largely unexplored. Here, we report that aPKC{iota} is highly expressed in human non-small cell lung cancer cell lines, whereas the closely related aPKC isozyme PKC{zeta} is undetectable in these cells. Disruption of PKC{iota} signaling reveals that PKC{iota} is dispensable for adherent growth of non-small cell lung cancer cells but is required for transformed growth in soft agar in vitro and for tumorigenicity in vivo. Molecular dissection of signaling down-stream of PKC{iota} demonstrates that Rac1 is a critical molecular target for PKC{iota}-dependent transformation, whereas PKC{iota} is not necessary for NF{kappa}B activation in vitro or in vivo. Expression of the PB1 domain of PKC{iota} (PKC{iota}-(1-113)) blocks PKC{iota}-dependent Rac1 activity and inhibits cellular transformation indicating a role for this domain in the transforming activity of PKC{iota}. Taken together, our data demonstrate that PKC{iota} is a critical lung cancer gene that activates a Rac1->Pak->Mek1,2->Erk1,2 signaling pathway required for transformed growth. Our data indicate that PKC{iota} may be an attractive molecular target for mechanism-based therapies for treatment of lung cancer.

Received for publication, May 17, 2005 , and in revised form, June 29, 2005.

* This work was supported by National Institutes of Health Grant CA81436 (to A. P. F.) and the Mayo Clinic Foundation. 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.

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


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