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Protein Kinase C Focusing at the cSMAC Is a Consequence rather than Cause of TCR Signaling and Is Dependent on the MEK/ERK Pathway¹

Kesavannair Praveen^*, Yan Zheng^*, Fabiola Rivas^* and Thomas F. Gajewski^2,*,

^* Department of Pathology and Department of Medicine, Committees on Immunology and Cancer Biology, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637

Correlation between protein kinase C focusing within the central supramolecular activation cluster (cSMAC) of the immunological synapse and optimal TCR/costimulatory receptor ligation was interpreted to imply that PKC focusing is required for productive signaling. However, this notion has been called into question and competing data suggest that the cSMAC contributes to receptor down-modulation. The observation that PKC focusing at the cSMAC is promoted by CD28 coligation, and also that it occurs late after proximal tyrosine phosphorylation events have been initiated, has led us to investigate an alternative possibility that PKC focusing might be a consequence rather than a cause of productive integrated signaling. Indeed, we found that inhibition of the downstream signaling molecules MEK and PI3K (but not of calcineurin, NF-B, JNK, or p38 MAPK) significantly prevented the focusing of PKC at the cSMAC. It recently has been suggested that the cSMAC may be associated with TCR degradation and signal termination. Using MEK inhibition as a tool, we observed that absence of detectable PKC focusing had no significant effect on TCR down-modulation or duration of CD3 phosphorylation. Our results suggest that PKC focusing at the cSMAC occurs as a consequence of productive integrated downstream signaling at least at the level of MEK. If PKC focusing accurately reflects the cSMAC as a whole, then our data also argue against the cSMAC as being required for proximal TCR signal termination.

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 National Institutes of Health Grant R01 AI47919.

² Address correspondence and reprint requests to Dr. Thomas F. Gajewski, Departments of Pathology and Medicine, Committees on Immunology and Cancer Biology, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637. E-mail address: tgajewsk{at}medicine.bsd.uchicago.edu

³ Abbreviations used in this paper: cSMAC, central supramolecular activation cluster; pSMAC, peripheral supramolecular activation cluster; PKC, protein kinase C.