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Molecular and Cellular Biology, March 2009, p. 1338-1353, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01359-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Ras Subcellular Localization Defines Extracellular Signal-Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins{triangledown}

Berta Casar,1 Imanol Arozarena,3 Victoria Sanz-Moreno,3 Adán Pinto,1 Lorena Agudo-Ibáñez,1 Richard Marais,3 Robert E. Lewis,4 María T. Berciano,2 and Piero Crespo1*

Departamento de Biología Molecular,1 Departamento de Anatomía y Biología Celular,2 Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Santander, 39011 Cantabria, Spain; Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, United Kingdom,3 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-76964

Received 27 August 2008/ Returned for modification 2 October 2008/ Accepted 17 December 2008

Subcellular localization influences the nature of Ras/extracellular signal-regulated kinase (ERK) signals by unknown mechanisms. Herein, we demonstrate that the microenvironment from which Ras signals emanate determines which substrates will be preferentially phosphorylated by the activated ERK1/2. We show that the phosphorylation of epidermal growth factor receptor (EGFr) and cytosolic phospholipase A2 (cPLA2) is most prominent when ERK1/2 are activated from lipid rafts, whereas RSK1 is mainly activated by Ras signals from the disordered membrane. We present evidence indicating that the underlying mechanism of this substrate selectivity is governed by the participation of different scaffold proteins that distinctively couple ERK1/2, activated at defined microlocalizations, to specific substrates. As such, we show that for cPLA2 activation, ERK1/2 activated at lipid rafts interact with KSR1, whereas ERK1/2 activated at the endoplasmic reticulum utilize Sef-1. To phosphorylate the EGFr, ERK1/2 activated at lipid rafts require the participation of IQGAP1. Furthermore, we demonstrate that scaffold usage markedly influences the biological outcome of Ras site-specific signals. These results disclose an unprecedented spatial regulation of ERK1/2 substrate specificity, dictated by the microlocalization from which Ras signals originate and by the selection of specific scaffold proteins.

* Corresponding author. Mailing address: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina, Santander, 39011 Cantabria, Spain. Phone: 34-942-200959. Fax: 34-942-201945. E-mail: crespop{at}unican.es

{triangledown} Published ahead of print on 29 December 2008.

Molecular and Cellular Biology, March 2009, p. 1338-1353, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01359-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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