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Molecular and Cellular Biology, February 2004, p. 1516-1530, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1516-1530.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of H-Ras in the Endoplasmic Reticulum by the RasGRF Family Guanine Nucleotide Exchange Factors

Imanol Arozarena,1,{dagger} David Matallanas,1,{dagger} María T. Berciano,2 Victoria Sanz-Moreno,1 Fernando Calvo,1 María T. Muñoz,3 Gustavo Egea,3 Miguel Lafarga,2 and Piero Crespo1*

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC), Departamento de Biología Molecular,1 Departamento de Anatomía y Biología Celular, Unidad de Biomedicina de la Universidad de Cantabria-CSIC, Santander 39011,2 Departament de Biología Cel-lular i Anatomia Patológica, Facultat de Medicina, Universitat de Barcelona-IDIBAPS, Barcelona 08036, Spain3

Received 14 July 2003/ Returned for modification 25 August 2003/ Accepted 14 November 2003

Recent findings indicate that in addition to its location in the peripheral plasma membrane, H-Ras is found in endomembranes like the endoplasmic reticulum and the Golgi complex. In these locations H-Ras is functional and can efficiently engage downstream effectors, but little is known about how its activation is regulated in these environments. Here we show that the RasGRF family exchange factors, both endogenous and ectopically expressed, are present in the endoplasmic reticulum but not in the Golgi complex. With the aid of H-Ras constructs specifically tethered to the plasma membrane, endoplasmic reticulum, and Golgi complex, we demonstrate that RasGRF1 and RasGRF2 can activate plasma membrane and reticular, but not Golgi-associated, H-Ras. We also show that RasGRF DH domain is required for the activation of H-Ras in the endoplasmic reticulum but not in the plasma membrane. Furthermore, we demonstrate that RasGRF mediation favors the activation of reticular H-Ras by lysophosphatidic acid treatment whereas plasma membrane H-Ras is made more responsive to stimulation by ionomycin. Overall, our results provide the initial insights into the regulation of H-Ras activation in the endoplasmic reticulum.

* Corresponding author. Mailing address: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Unidad de Biomedicina de la Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina, C/ Cardenal Herrera Oria s/n, Santander 39011, Spain. Phone: 34-942-200959. Fax: 34-942-201945. E-mail: pcrespo{at}iib.uam.es.

{dagger} I.A. and D.M. contributed equally to this study.

Molecular and Cellular Biology, February 2004, p. 1516-1530, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1516-1530.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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