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J. Biol. Chem., Vol. 279, Issue 21, 22118-22123, May 21, 2004

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Protein Kinase C (PKC) II Induces Cell Invasion through a Ras/Mek-, PKC/Rac 1-dependent Signaling Pathway^*

Jie Zhang, Panos Z. Anastasiadis, Yan Liu, E. Aubrey Thompson, and Alan P. Fields

From the Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224

Protein kinase C II (PKCII) promotes colon carcinogenesis. Expression of PKCII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCII. Here we show that RIE/PKCII cells acquire an invasive phenotype that is blocked by the PKC inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCII, indicating that PKCII activity is required for the invasive phenotype. PKCII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCII cells. PKCII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKC. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical downstream effector of PKCII-mediated invasion. Taken together, our results define a novel PKCII Ras PKC /Rac1 Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCII promotes colon carcinogenesis.

Received for publication, January 23, 2004 , and in revised form, March 17, 2004.

^* 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.

To whom correspondence should be addressed: The 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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