title: Atypical protein kinase Czeta suppresses migration of mouse melanoma cells.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sanz-Navares
authors.forename: N
authors.initials: N
authors.lastname: Fernandez
authors.forename: M G
authors.initials: MG
authors.lastname: Kazanietz
authors.forename: S A
authors.initials: SA
authors.lastname: Rotenberg
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins / Q000096:biosynthesis; D008546:Melanoma, Experimental; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009362:Neoplasm Metastasis; D010649:Phenylalanine / Q000378:metabolism; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D010649:Phenylalanine; D011493:Protein Kinase C; D014443:Tyrosine; D000099221:Protein Kinase C zeta; C101296:prostate apoptosis response-4 protein