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Molecular and Cellular Biology, September 2004, p. 7643-7653, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7643-7653.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of Atypical Protein Kinase C in Estradiol-Triggered G1/S Progression of MCF-7 Cells

Gabriella Castoria,1 Antimo Migliaccio,1 Marina Di Domenico,1 Maria Lombardi,1 Antonietta de Falco,1 Lilian Varricchio,1 Antonio Bilancio,1 Maria Vittoria Barone,2 and Ferdinando Auricchio1*

Dipartimento di Patologia Generale-Facoltà di Medicina e Chirurgia, II Università di Napoli,1 Istituto Nazionale per lo Studio e la Cura dei Tumori-Fondazione "Giovanni Pascale," Naples, Italy2

Received 23 January 2004/ Returned for modification 7 March 2004/ Accepted 1 June 2004

Expression of a dominant negative atypical protein kinase C (aPKC), PKC{zeta}, 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 (hER{alpha}), 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 PKC{zeta} by Thr410 phosphorylation. Serine phosphorylation of PKC{zeta} is simultaneously induced. PKC{zeta} activation leads to recruitment of Ras to a multimolecular complex that also includes hER{alpha}, Src, PI 3-kinase, and aPKC. We propose that PKC{zeta} 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.

* Corresponding author. Mailing address: Dipartimento di Patologia Generale-Facoltà di Medicina e Chirurgia, II Università di Napoli, Via L. De Crecchio, 80138 Naples, Italy. Phone: 39 081 5665676. Fax: 39 081 291327. E-mail: ferdinando.auricchio{at}unina2.it.

Molecular and Cellular Biology, September 2004, p. 7643-7653, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7643-7653.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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