Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, and multiple autoimmune disorders. Here, we identify a signaling pathway that is exclusively responsible for inflammatory cytokine production but not for cytotoxicity. Recognition of H60+ or CD137L+ tumor cells by murine NK cells led to efficient cytotoxicity and inflammatory cytokine production. Both of these effector functions required Lck, Fyn, PI(3)K-p85α, PI(3)K-p110δ, and PLC-γ2. However, the complex of Fyn and the adapter ADAP exclusively regulated inflammatory cytokine production but not cytotoxicity in NK cells. This unique function of ADAP required a Carma1-Bcl10-MAP3K7 signaling axis. Our results identify molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.

The intracellular spatiotemporal organization of signaling events is critical for normal cellular function. In response to environmental stimuli, cells utilize highly organized signaling pathways that are subject to multiple layers of regulation. However, the molecular mechanisms that coordinate these complex processes remain an enigma. Scaffolding proteins (scaffolins) have emerged as critical regulators of signaling pathways, many of which have well-described functions in immune cells. IQGAP1, a highly conserved cytoplasmic scaffold protein, is able to curb, compartmentalize, and coordinate multiple signaling pathways in a variety of cell types. IQGAP1 plays a central role in cell-cell interaction, cell adherence, and movement via actin/tubulin-based cytoskeletal reorganization. Evidence also implicates IQGAP1 as an essential regulator of the MAPK and Wnt/β-catenin signaling pathways. Here, we summarize the recent advances on the cellular and molecular biology of IQGAP1. We also describe how this pleiotropic scaffolin acts as a true molecular puppeteer, and highlight the significance of future research regarding the role of IQGAP1 in immune cells.

Activating and inhibiting receptors of lymphocytes collect valuable information about their mikròs kósmos. This information is essential to initiate or to turn off complex signaling pathways. Irrespective of these advances, our knowledge on how these intracellular activation cascades are coordinated in a spatiotemporal manner is far from complete. Amongst multiple explanations, the scaffolding proteins have emerged as a critical piece of this evolutionary tangram. Amongst many, IQGAP1 is one of the essential scaffolding proteins that coordinate multiple signaling pathways. IQGAP1 possesses multiple protein interaction motifs to achieve its scaffolding functions. Using these domains, IQGAP1 has been shown to regulate a number of essential cellular events. This includes actin polymerization, tubulin multimerization, MTOC formation, calcium/calmodulin signaling, Pak/Raf/Mek1/2-mediated Erk1/2 activation, formation of maestrosome, E-cadherin and CD44-mediated signaling and GSK3/APC-mediated β-catenin activation. In this review we summarize the recent developments and exciting new findings of cellular functions of IQGAP1.

In the version of this article initially published, the second affiliation for Stephanie C. Ganal is missing. This author is also affiliated with the Spemann Graduate School of Biology and Medicine, Freiburg, Germany. The error has been corrected in the HTML and PDF versions of the article.Corrigendum: Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells In the version of this article initially published online, the affiliation of author Bart Vanhaesebroeck was incorrect. The correct affiliation is as follows: Center for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, London, UK. The error has been corrected for the print, PDF and HTML versions of this article. Erratum: Matching cellular dimensions with molecular sizes Michael Reth Nat. Immunol. 14, 765-767 (2013)In the version of this article originally posted online, the units in the text referring to Figure 1a were incorrect. The correct unit is "μm" and the correct text is " the receptor depicted would measure about 3 μm, compared with a resting B lymphocyte, with an average diameter of about 7 μm. " The error has been corrected in this file as of 22 August 2013.Erratum: The role of the immune system in governing host-microbe interactions in the intestine In the version of this article initially published, a label was missing from Figure 2. The lymphoid structure in the large intestine should be labeled 'Isolated lymphoid follicle' . The error has been corrected in the HTML and PDF versions of the article.c o r r i g e n d a a n d e r r ata npg

‘Cytokine release syndrome’ (CRS) is a serious side effect of NK or T cell-mediated immunotherapy to treat cancer. A strategy to contain CRS without affecting the cytotoxic potential of NK and T cells is highly warranted. A thorough understanding of the signaling pathways will help to identify molecules that exclusively regulate inflammatory cytokine production but not cytotoxicity. Here, we define an ADAP-dependent signaling axis downstream of Fyn that exclusively regulated cytokine production but not cytotoxicity in NK cells. The adapter protein, ADAP is critical for organizing the Carma1-Bcl10-MALT1 signalosome, which is essential for the activation of TAK1. The initiation of these signaling events is critical for the production of Interferon-γ and other pro-inflammatory cytokines. The defect in cytokine production correlated with a decreased nuclear translocation of c-Fos and c-Jun despite a significantly increased phosphorylation of ERK1/2 and JNK1/2 in the ADAP deficient NK cells. Nuclear translocation of NFκB was also decreased in the ADAP deficient NK cells. Our findings indicate that ADAP is indispensible for activating a signaling cascade that leads to inflammatory cytokine production, whereas it is not essential for those signaling events that lead to cytotoxicity. Our findings demonstrate the feasibility of targeting the functions of unique signaling molecules in order to regulate the production of inflammatory cytokines.