Atypical protein kinase Czeta 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)zeta to low levels. Although control experiments rule out a direct role by melanin, PKCzeta down-regulation is shown to be a critical determinant of cell migration. Transfection of high-motility cells with either wild-type PKCzeta or its regulatory domain suppresses migration. Known to bind to the regulatory domain of PKCzeta, the proapoptotic protein prostate apoptosis response-4 (Par-4) coimmunoprecipitates with PKCzeta 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 PKCzeta), whereas high-motility cells (which express low levels of PKCzeta) are unaffected by Par-4 overexpression. It is proposed that in nonmetastatic cells, the PKCzeta Par-4 complex provides a brake on migration that is released by melanin precursors that initiate PKCzeta down-regulation. Elevation of PKCzeta in melanoma cells, or preventing its down-regulation through the dietary restriction of tyrosine and phenylalanine, may therefore control metastatic behavior.