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J. Biol. Chem., Vol. 279, Issue 5, 3300-3307, January 30, 2004

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Requirement of Protein Kinase Cµ Activation and Calpain-mediated Proteolysis for Arachidonic Acid-stimulated Adhesion of MDA-MB-435 Human Mammary Carcinoma Cells to Collagen Type IV^*

Sarah B. Kennett, John D. Roberts, and Kenneth Olden

From the Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Arachidonic acid (AA) stimulation of adhesion of human metastatic breast carcinoma cells to collagen type IV depends on the protein kinase C (PKC) pathway(s) and is associated with the translocation of PKCµ from the cytoplasm to the membrane. In the present study, we have further explored the role of PKCµ in AA-stimulated adhesion. PKCµ activation site serines 738/742 and autophosphorylation site serine 910 are rapidly phosphorylated, and in vitro PKCµ kinase activity is enhanced in response to AA treatment. Inhibition of PKCµ activation blocks AA-stimulated adhesion. A phosphorylated, truncated species of PKCµ was detected in AA-treated cells. This 77-kDa protein contains the kinase domain but lacks a significant portion of the regulatory domains. Inhibition of calpain protease activity blocks generation of the truncated protein, promotes accumulation of the activated, full-length protein in the membrane, and blocks the AA-mediated increase in adhesion. p38 MAPK activity is also required for AA-stimulated adhesion. Activation of PKCµ and p38 are independent events. However, inhibition of p38 activity reduces calpain-mediated proteolysis of PKCµ and in vivo calpain activity, suggesting a role for p38 in regulation of calpain activity and a point for cross-talk between the PKC and MAPK pathways. These results support the hypothesis that AA stimulates activation of PKCµ, which is cleaved by calpain at the cell membrane. The resulting truncated kinase, as well as the full-length kinase, may be required for increased cell adhesion to collagen type IV. Additionally, these studies present the first evidence for calpain cleavage of a non-structural protein leading to the promotion of tumor cell adhesion.

Received for publication, June 2, 2003 , and in revised form, October 17, 2003.

^* 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: P.O. Box 12233, Mail Drop C2-14, Research Triangle Park, NC 27709. Tel.: 919-541-5023; Fax: 919-541-0146; E-mail: roberts1{at}niehs.nih.gov.

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