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Sci. Signal., 13 March 2012
Vol. 5, Issue 215, p. ra21
[DOI: 10.1126/scisignal.2002351]

RESEARCH ARTICLES

Regulation of the EGF Transcriptional Response by Endocytic Sorting

Ben Brankatschk1*, Sven P. Wichert2, Shem D. Johnson1, Olivier Schaad1,3, Moritz J. Rossner2, and Jean Gruenberg1{dagger}

1 Department of Biochemistry, University of Geneva, 30 Quai E. Ansermet, 1211 Geneva 4, Switzerland.
2 Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Goettingen, Germany.
3 Genomics Platform, CMU, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland.

* Present address: Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Goettingen, Germany.

Abstract: Ligand binding to the epidermal growth factor receptor (EGFR) on the cell surface activates the extracellular signal–regulated kinase (ERK) cascade. Activated, ligand-bound receptors are internalized, and this process may contribute to termination of signaling or enable signaling from intracellular sites. ESCRT (endosomal sorting complex required for transport) complexes may contribute to termination of signaling by sorting receptors into intraluminal vesicles of multivesicular endosomes from which the receptors continue into lysosomes for degradation. We showed that depletion of ESCRTs, which causes the retention of the EGFR in endosomes, increased the activation of the EGFR and its downstream kinases but had little effect on the overall profile and amplitude of the EGF-induced transcriptional response. In contrast, interfering with receptor endocytosis or ubiquitination to keep the EGFR at the cell surface stimulated increases in the abundance of many EGF-induced transcripts, similar to those induced by EGFR overexpression. We also found that the complete EGF transcriptional program was rapidly activated after ligand binding to the receptor. We conclude that the transcriptional response is elicited primarily by receptor molecules at the cell surface.

{dagger} To whom correspondence should be addressed. E-mail: jean.gruenberg{at}unige.ch

Citation: B. Brankatschk, S. P. Wichert, S. D. Johnson, O. Schaad, M. J. Rossner, J. Gruenberg, Regulation of the EGF Transcriptional Response by Endocytic Sorting. Sci. Signal. 5, ra21 (2012).

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