Atypical Protein Kinase C{zeta} Suppresses Migration of Mouse Melanoma Cells

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 highmotility 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 downregulation through the dietary restriction of tyrosine and phenylalanine, may therefore control metastatic behavior.