This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Google Scholar Google Scholar Articles by Sanz-Navares, E. Articles by Rotenberg, S. A. Search for Related Content PubMed PubMed Citation Articles by Sanz-Navares, E. Articles by Rotenberg, S. A.

Atypical Protein Kinase C Suppresses Migration of Mouse Melanoma Cells¹

Department of Chemistry and Biochemistry [E. S-N., S. A. R.] and Graduate Center [E. S-N.], Queens College of the City University of New York, Flushing, New York 11367, and Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [N. F., M. G. K.]

Mouse melanoma B16 F1 cells cultured in RPMI 1640 supplemented with the melanin precursors tyrosine and phenylalanine display increased melanin levels and elevated migration while down-regulating protein kinase C (PKC) to low levels. Although control experiments rule out a direct role by melanin, PKC down-regulation is shown to be a critical determinant of cell migration. Transfection of high-motility cells with either wild-type PKC or its regulatory domain suppresses migration. Known to bind to the regulatory domain of PKC, the proapoptotic protein prostate apoptosis response-4 (Par-4) coimmunoprecipitates with PKC as a 47-kDa protein. Transfection of Par-4 (or its leucine zipper element) further suppresses migration of low-motility cells (which express high levels of PKC), whereas high-motility cells (which express low levels of PKC) are unaffected by Par-4 overexpression. It is proposed that in nonmetastatic cells, the PKC Par-4 complex provides a brake on migration that is released by melanin precursors that initiate PKC down-regulation. Elevation of PKC in melanoma cells, or preventing its down-regulation through the dietary restriction of tyrosine and phenylalanine, may therefore control metastatic behavior.