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The IREM-1 (CD300f) Inhibitory Receptor Associates with the p85 Subunit of Phosphoinositide 3-Kinase¹

Molecular Immunopathology Unit, Department de Ciéncies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

The immune receptor expressed by myeloid cell 1 (IREM-1) (CD300f) inhibitory receptor displays five cytoplasmic tyrosine residues, two of them (Y205 and Y249) fit with ITIMs, whereas Y236 and Y263 constitute putative binding sites for PI3K. In the present study, immunoprecipitation analysis revealed that both the p85 subunit of PI3K and Src homology region 2 domain-containing phosphatase-1 could be recruited by IREM-1 in transfected cells as well as in the U937 monocytic leukemia cells, which constitutively express the receptor. By assaying the ability of different IREM-1 mutants to regulate the secretion of -hexosaminidase induced via FcRI in rat basophilic leukemia cells, both Y205 and Y249 appeared crucial for IREM-1-mediated inhibition. Remarkably, engagement of an IREM-1 mutant (Y_205,249,284F), which did not recruit Src homology region 2 domain-containing phosphatase-1 and lost its inhibitory function, induced rat basophilic leukemia cell degranulation. This effect was dependent on the recruitment of PI3K, requiring the integrity of Y236 and Y263, and was blocked by PI3K inhibitors (i.e., wortmannin and LY-294002). Altogether, these data reveal a putative functional duality of the IREM-1 myeloid cell receptor.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Plan Nacional de I+D (SAF2001-0696). D.A.-E. is supported by a fellowship from the Ministerio de Ciencia y Tecnología, and J.S. is supported by a contract Ramon y Cajal from Ministerio de Ciencia y Tecnología.

² J.S. and M.L.-B. share equal credit for senior authorship.

³ Address correspondence and reprint requests to Dr. Joan Sayós, Molecular Immunopathology Unit, DCEXS, Universitat Pompeu Fabra, Doctor Aiguader 80, 08003 Barcelona, Spain; E-mail address: joan.sayos{at}upf.edu or Dr. Miguel López-Botet, Molecular Immunopathology Unit, DCEXS, Universitat Pompeu Fabra, Doctor Aiguader 80, 08003 Barcelona, Spain; E-mail address: miguel.lopez-botet{at}upf.edu

⁴ Abbreviations used in this paper: SH, Src homology; SHP, Src homology region 2 domain-containing phosphatase; IREM, immune receptor expressed by myeloid cells; abs, absorbance; PtdIns-3,4,5 P₃, phosphatidylinositol-3,4,5-trisphosphate; RBL, rat basophilic leukemia; HA, hemagglutinin; ILT, Ig-like transcript.