Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells.
Expression of a dominant negative atypical protein kinase C (aPKC), PKCzeta, prevents nuclear translocation of extracellular regulated kinase 2 (ERK-2), p27 nuclear reduction, and DNA synthesis induced by estradiol in human mammary cancer-derived MCF-7 cells. aPKC action upstream of these events has been analyzed. In hormone-stimulated NIH 3T3 and Cos cells ectopically expressing human estrogen receptor alpha (hERalpha), aPKC is activated by phosphatidylinositol 3-kinase (PI 3-kinase) and, in turn, controls the Ras/MEK-1/ERK cascade. In MCF-7 and Cos cells stimulated by hormone, PI 3-kinase activates PKCzeta by Thr410 phosphorylation. Serine phosphorylation of PKCzeta is simultaneously induced. PKCzeta activation leads to recruitment of Ras to a multimolecular complex that also includes hERalpha, Src, PI 3-kinase, and aPKC. We propose that PKCzeta pushes Ras and the signaling complex close together in such a way that it facilitates the Src-dependent Ras activation. This activation is crucial for the interplay between estradiol-triggered signaling and cell cycle machinery.
Dipartimento di Patologia Generale-Facoltà di Medicina e Chirurgia, II Università di Napoli, Via L. De Crecchio, 80138 Naples, Italy.
Gabriella
G
Castoria
Antimo
A
Migliaccio
Marina
M
Di Domenico
Maria
M
Lombardi
Antonietta
A
de Falco
Lilian
L
Varricchio
Antonio
A
Bilancio
Maria Vittoria
MV
Barone
Ferdinando
F
Auricchio
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099221:Protein Kinase C zeta
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D019950:Mitogen-Activated Protein Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D021122:Protein Subunits; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; D019061:src-Family Kinases; D000099221:Protein Kinase C zeta; C493961:Cdkn1b protein, mouse