HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shahjahan Miah, S. M. Articles by Campbell, K. S. Search for Related Content PubMed PubMed Citation Articles by Shahjahan Miah, S. M. Articles by Campbell, K. S.

KIR2DL4 Differentially Signals Downstream Functions in Human NK Cells through Distinct Structural Modules¹

Fox Chase Cancer Center, Division of Basic Science, Institute for Cancer Research, Philadelphia, PA 19111

KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IB kinase β (IKKβ) and the phosphorylation and degradation of IB, which indicate activation of the classical NF-B pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-, IFN-, MIP1, MIP1β, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-, IL-8, and MIP1 production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-B. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcRI- association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-B pathway and selectively stimulated the production of MIP1, but not that of IFN- or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcRI-; and 2) through another receptor domain independent of the transmembrane arginine.

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 Grant CA100226 (to K.S.C) and partially by Centers of Research Excellence Grant CA06927 from the National Institutes of Health. This work was also supported in part by an appropriation from the Commonwealth of Pennsylvania. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

² Address correspondence and reprint requests to Dr. Kerry S. Campbell, Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: kerry.campbell{at}fccc.edu

³ Abbreviations used in this paper: KIR, killer cell Ig-like receptor; 2DL4, KIR2DL4 (KIR with two Ig-like domains and a long cytoplasmic domain); IKK, IB kinase; p90RSK, p90 ribosomal S6 kinase; R/G, transmembrane arginine to glycine mutation; WT, wild type.