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P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer

Oncogene volume 30, pages 1059–1071 (2011)Cite this article

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Abstract

The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and Gβγ activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Innovation of Spain (BFU2006-01813/BMC and BFU2009-07728/BMC) and by the Consejería de Sanidad de la JCYL. JCM receives support from the Cancer Center Network Program from the ISCIII (RD06/0020/0041), and SS from the Juan de la Cierva Program. Our Cancer Research Institute, and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces. We thank Drs Heidi CE Welch and Mikio Hoshino for providing the myc-tagged P-Rex1 and an anti-P-Rex antibody, respectively.

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  1. J C Montero and S Seoane: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

    J C Montero, S Seoane & A Pandiella

  2. Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, and AECC Unit, Albacete, Spain

    A Ocaña

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  1. J C Montero
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  2. S Seoane
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  4. A Pandiella
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Correspondence to A Pandiella.

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Montero, J., Seoane, S., Ocaña, A. et al. P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer. Oncogene 30, 1059–1071 (2011). https://doi.org/10.1038/onc.2010.489

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