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Molecular and Cellular Biology, June 2009, p. 3332-3343, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01955-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cell Density-Dependent Inhibition of Epidermal Growth Factor Receptor Signaling by p38{alpha} Mitogen-Activated Protein Kinase via Sprouty2 Downregulation{triangledown}

Aneta Swat,1,{dagger} Ignacio Dolado,1*,{dagger} Jose Maria Rojas,2 and Angel R. Nebreda1*

CNIO (Spanish National Cancer Centre), Melchor Fernandez Almagro 3, 28029 Madrid, Spain,1 Centro Nacional de Microbiologia, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain2

Received 27 December 2008/ Returned for modification 3 February 2009/ Accepted 6 April 2009

Contact inhibition is a fundamental process in multicellular organisms aimed at inhibiting proliferation at high cellular densities through poorly characterized intracellular signals, despite availability of growth factors. We have previously identified the protein kinase p38{alpha} as a novel regulator of contact inhibition, as p38{alpha} is activated upon cell-cell contacts and p38{alpha}-deficient cells are impaired in both confluence-induced proliferation arrest and p27Kip1 accumulation. Here, we establish that p27Kip1 plays a key role downstream of p38{alpha} to arrest proliferation at high cellular densities. Surprisingly, p38{alpha} does not directly regulate p27Kip1 expression levels but leads indirectly to confluent upregulation of p27Kip1 and cell cycle arrest via the inhibition of mitogenic signals originating from the epidermal growth factor receptor (EGFR). Hence, confluent activation of p38{alpha} uncouples cell proliferation from mitogenic stimulation by inducing EGFR degradation through downregulation of the EGFR-stabilizing protein Sprouty2 (Spry2). Accordingly, confluent p38{alpha}-deficient cells fail to downregulate Spry2, providing them in turn with sustained EGFR signaling that facilitates cell overgrowth and oncogenic transformation. Our results provide novel mechanistic insight into the role of p38{alpha} as a sensor of cell density, which induces confluent cell cycle arrest via the Spry2-EGFR-p27Kip1 network.

* Corresponding author. Mailing address: CNIO (Spanish National Cancer Centre), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Phone: 34-917328000. Fax: 34-917328033. E-mail for Angel R. Nebreda: anebreda{at}cnio.es. E-mail for Ignacio Dolado: idolado{at}gmail.com

{triangledown} Published ahead of print on 13 April 2009.

{dagger} These authors equally contributed to this work.

Molecular and Cellular Biology, June 2009, p. 3332-3343, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01955-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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