Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 7962K) PDF+supp data (10951K) PPT slides of all figures Supplemental Material Related biobytes podcast Alert me when this article is cited View original image data Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Vijayaraj, P. Articles by Magin, T. M. PubMed PubMed Citation Articles by Vijayaraj, P. Articles by Magin, T. M. Related Collections Related Article Social Bookmarking                            What's this?

Keratins regulate protein biosynthesis through localization of GLUT1 and -3 upstream of AMP kinase and Raptor

¹ Abteilung für Zellbiochemie, Institut für Biochemie und Molekularbiologie and ² Bonner Forum Biomedizin, Universität Bonn, 53115 Bonn, Germany
³ Institut für Molekulare und Zelluläre Anatomie, Rheinisch-Westfälische Technische Hochschule Aachen Universität, 52074 Aachen, Germany
⁴ Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Correspondence to Thomas M. Magin: t.magin{at}uni-bonn.de

Keratin intermediate filament proteins form cytoskeletal scaffolds in epithelia, the disruption of which affects cytoarchitecture, cell growth, survival, and organelle transport. However, owing to redundancy, the global function of keratins has not been defined in full. Using a targeted gene deletion strategy, we generated transgenic mice lacking the entire keratin multiprotein family. In this study, we report that without keratins, embryonic epithelia suffer no cytolysis and maintain apical polarity but display mislocalized desmosomes. All keratin-null embryos die from severe growth retardation at embryonic day 9.5. We find that GLUT1 and -3 are mislocalized from the apical plasma membrane in embryonic epithelia, which subsequently activates the energy sensor adenosine monophosphate kinase (AMPK). Analysis of the mammalian target of rapamycin (mTOR) pathway reveals that AMPK induction activates Raptor, repressing protein biosynthesis through mTORC1's downstream targets S6 kinase and 4E-binding protein 1. Our findings demonstrate a novel keratin function upstream of mTOR signaling via GLUT localization and have implications for pathomechanisms and therapy approaches for keratin disorders and the analysis of other gene families.

Abbreviations used in this paper: 4E-BP1, 4E-binding protein 1; AMPK, AMP kinase; E-cadherin, epithelial cadherin; ES, embryonic stem; KO, knockout; MICER, Mutagenic Insertion and Chromosome Engineering Resource; mTOR, mammalian target of rapamycin; S6K, S6 kinase; WT, wild type.

© 2009 Vijayaraj et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Kellner, J. C., Coulombe, P. A. (2009). Keratins and protein synthesis: the plot thickens. JCB 187: 157-159 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents