HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 38, 32856-32865, September 23, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/38/32856    most recent M506119200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Calautti, E. Articles by Goetinck, P. F. Search for Related Content PubMed PubMed Citation Articles by Calautti, E. Articles by Goetinck, P. F. Social Bookmarking                      What's this?

Phosphoinositide 3-Kinase Signaling to Akt Promotes Keratinocyte Differentiation Versus Death^*

From the Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Signaling pathways regulating the differentiation program of epidermal cells overlap widely with those activated during apoptosis. How differentiating cells remain protected from premature death, however, is still poorly defined. We show here that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated at early stages of mouse keratinocyte differentiation both in culture and in the intact epidermis in vivo. Expression of active Akt in keratinocytes promotes growth arrest and differentiation, whereas pharmacological blockade of PI3K inhibits the expression of "late" differentiation markers and leads to death of cells that would otherwise differentiate. Mechanistically, the activation of the PI3K/Akt pathway in keratinocyte differentiation depends on the activity of the epidermal growth factor receptor and Src families of tyrosine kinases and the engagement of E-cadherin-mediated adhesion. During this process, PI3K associates increasingly with cadherin-catenin protein complexes bearing tyrosine phosphorylated YXXM motifs. Thus, the PI3K signaling pathway regulates the choice between epidermal cell differentiation and death at the cross-talk between tyrosine kinases and cadherin-associated catenins.

Received for publication, June 6, 2005 , and in revised form, July 15, 2005.

^* This work was supported by National Institutes of Health Grants HD-37490 (to P. F. G.) and AR45284 (to J. L. B.) and in part by The Veneto Eye Bank Foundation and the Telethon Foundation (Italy). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Epithelial Stem Cell Research Center, The Veneto Eye Bank Foundation, Ospedale Civile di Venezia, Castello 6777, 30122 Venice, Italy.

³ Supported by the Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd. Agreement.

¹ To whom correspondence should be addressed: Epithelial Stem Cell Research Center, The Veneto Eye Bank Foundation, Ospedale Civile di Venezia, Castello 6777, 30122 Venice, Italy. Tel.: 39-041-529-5822; Fax: 39-041-529-5825; E-mail: enzo.calautti{at}cbrc2.mgh.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Yao, C. L. Alexander, J. A. Quinn, W.-C. Chan, H. Wu, and D. A. Greenhalgh Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21WAF-induced differentiation triggered by GSK3{beta} inactivation and reduced AKT activity J. Cell Sci., May 15, 2008; 121(10): 1758 - 1769. [Abstract] [Full Text] [PDF]

				A.-C. Feutz, Y. Barrandon, and D. Monard Control of thrombin signaling through PI3K is a mechanism underlying plasticity between hair follicle dermal sheath and papilla cells J. Cell Sci., May 1, 2008; 121(9): 1435 - 1443. [Abstract] [Full Text] [PDF]

				C.-L. Tu, W. Chang, Z. Xie, and D. D. Bikle Inactivation of the Calcium Sensing Receptor Inhibits E-cadherin-mediated Cell-Cell Adhesion and Calcium-induced Differentiation in Human Epidermal Keratinocytes J. Biol. Chem., February 8, 2008; 283(6): 3519 - 3528. [Abstract] [Full Text] [PDF]

				A. R. Tan, S. M. Steinberg, A. L. Parr, D. Nguyen, and S. X. Yang Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment Ann. Onc., January 1, 2008; 19(1): 185 - 190. [Abstract] [Full Text] [PDF]

				R. F.L. O'Shaughnessy, B. Akgul, A. Storey, H. Pfister, C. A. Harwood, and C. Byrne Cutaneous Human Papillomaviruses Down-regulate AKT1, whereas AKT2 Up-regulation and Activation Associates with Tumors Cancer Res., September 1, 2007; 67(17): 8207 - 8215. [Abstract] [Full Text] [PDF]

				R. F. L. O'Shaughnessy, J. C. Welti, J. C. Cooke, A. A. Avilion, B. Monks, M. J. Birnbaum, and C. Byrne AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation J. Biol. Chem., June 8, 2007; 282(23): 17297 - 17305. [Abstract] [Full Text] [PDF]

				E. A. Waterman, N. Sakai, N. T. Nguyen, B. A.J. Horst, D. P. Veitch, C. N. Dey, S. Ortiz-Urda, P. A. Khavari, and M. P. Marinkovich A Laminin-Collagen Complex Drives Human Epidermal Carcinogenesis through Phosphoinositol-3-Kinase Activation Cancer Res., May 1, 2007; 67(9): 4264 - 4270. [Abstract] [Full Text] [PDF]

				Z. Xie and D. D. Bikle The Recruitment of Phosphatidylinositol 3-Kinase to the E-cadherin-Catenin Complex at the Plasma Membrane Is Required for Calcium-induced Phospholipase C-{gamma}1 Activation and Human Keratinocyte Differentiation J. Biol. Chem., March 23, 2007; 282(12): 8695 - 8703. [Abstract] [Full Text] [PDF]

				G. F. Weber and A. S. Menko Phosphatidylinositol 3-kinase is necessary for lens fiber cell differentiation and survival. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4490 - 4499. [Abstract] [Full Text] [PDF]

				C. W. Menges, L. A. Baglia, R. Lapoint, and D. J. McCance Human Papillomavirus Type 16 E7 Up-regulates AKT Activity through the Retinoblastoma Protein Cancer Res., June 1, 2006; 66(11): 5555 - 5559. [Abstract] [Full Text] [PDF]

				B. R. Thrash, C. W. Menges, R. H. Pierce, and D. J. McCance AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes J. Biol. Chem., April 28, 2006; 281(17): 12155 - 12162. [Abstract] [Full Text] [PDF]

				M. Sadagurski, S. Yakar, G. Weingarten, M. Holzenberger, C. J. Rhodes, D. Breitkreutz, D. LeRoith, and E. Wertheimer Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol. Cell. Biol., April 1, 2006; 26(7): 2675 - 2687. [Abstract] [Full Text] [PDF]