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Biochim Biophys Acta. 2016 Nov;1863(11):2758-2765. doi: 10.1016/j.bbamcr.2016.08.012. Epub 2016 Aug 24.

Ph(-) myeloproliferative neoplasm red blood cells display deregulation of IQGAP1-Rho GTPase signaling depending on CALR/JAK2 status.

Author information

1
TheREx Team "Thérapeutique recombinante expérimentale", TIMC-IMAG Laboratory, "Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble", UMR, UJF, CNRS 5525, University of Grenoble Alpes, France. Electronic address: nuriasocoro@gmail.com.
2
TheREx Team "Thérapeutique recombinante expérimentale", TIMC-IMAG Laboratory, "Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble", UMR, UJF, CNRS 5525, University of Grenoble Alpes, France.
3
Plateforme Protéomique de la Génopole Toulouse Midi-Pyrénées, Institut de Pharmacologie et de Biologie Structurale, CNRS, UMR, 5089 Toulouse, France.
4
Department of clinical proteomics, University of Geneva, Switzerland.
5
INSERM, UMR1170, Gustave Roussy, Université Paris-Sud, Villejuif, France.
6
TheREx Team "Thérapeutique recombinante expérimentale", TIMC-IMAG Laboratory, "Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble", UMR, UJF, CNRS 5525, University of Grenoble Alpes, France; Clinique Universitaire d'Hématologie, Grenoble Alpes University Hospital, France.
7
TheREx Team "Thérapeutique recombinante expérimentale", TIMC-IMAG Laboratory, "Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble", UMR, UJF, CNRS 5525, University of Grenoble Alpes, France; Laboratoire d'Hématologie cellulaire, Institut de Biologie et Pathologie, Grenoble Alpes University Hospital, France.

Abstract

Besides genetic abnormalities in MPN patients, several studies have reported alterations in protein expression that could contribute towards the clinical phenotype. However, little is known about protein modifications in Ph- MPN erythrocytes. In this context, we used a quantitative mass spectrometry proteomics approach to study the MPN erythrocyte proteome. LC-MS/MS (LTQ Orbitrap) analysis led to the identification of 51 and 86 overexpressed proteins in Polycythemia Vera and Essential Thrombocythemia respectively, compared with controls. Functional comparison using pathway analysis software showed that the Rho GTPase family signaling pathways were deregulated in MPN patients. In particular, IQGAP1 was significantly overexpressed in MPNs compared with controls. Additionally, Western-blot analysis not only confirmed IQGAP1 overexpression, but also showed that IQGAP1 levels depended on the patient's genotype. Moreover, we found that in JAK2V617F patients IQGAP1 could bind RhoA, Rac1 and Cdc42 and consequently recruit activated GTP-Rac1 and the cytoskeleton motility protein PAK1. In CALR(+) patients, IQGAP1 was not overexpressed but immunoprecipitated with RhoGDI. In JAK2V617F transduced Ba/F3 cells we confirmed JAK2 inhibitor-sensitive overexpression of IQGAP1/PAK1. Altogether, our data demonstrated alterations of IQGAP1/Rho GTPase signaling in MPN erythrocytes dependent on JAK2/CALR status, reinforcing the hypothesis that modifications in erythrocyte signaling pathways participate in Ph- MPN pathogenesis.

KEYWORDS:

Erythrocyte proteome; IQGAP1; Myeloproliferative neoplasms; Rho GTPases

PMID:
27566291
DOI:
10.1016/j.bbamcr.2016.08.012
[Indexed for MEDLINE]
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