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J. Biol. Chem., Vol. 282, Issue 17, 12397-12409, April 27, 2007

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The C-type Lectin Receptors CLEC-2 and Dectin-1, but Not DC-SIGN, Signal via a Novel YXXL-dependent Signaling Cascade^*

Gemma L. J. Fuller¹, Jennifer A. E. Williams, Michael G. Tomlinson², Johannes A. Eble³, Sheri L. Hanna^¶, Stefan Pöhlmann^||, Katsue Suzuki-Inoue^**, Yukio Ozaki^**, Steve P. Watson⁴, and Andrew C. Pearce⁵

From the Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom, Institute for Physiological Chemistry and Pathobiochemistry, Muenster University Hospital, 48149 Muenster, Germany, the ^¶Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ^||Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany, and the ^**Department of Clinical and Laboratory Medicine, University of Yamanashi, 1110 Shimokato Tamaho Nakakoma, Yamanashi 409-3898, Japan

The two lectin receptors, CLEC-2 and Dectin-1, have been shown to signal through a Syk-dependent pathway, despite the presence of only a single YXXL in their cytosolic tails. In this study, we show that stimulation of CLEC-2 in platelets and in two mutant cell lines is dependent on the YXXL motif and on proteins that participate in signaling by immunoreceptor tyrosine-based activation motif receptors, including Src, Syk, and Tec family kinases, and on phospholipase C. Strikingly, mutation of either Src homology (SH) 2 domain of Syk blocks signaling by CLEC-2 despite the fact that it has only a single YXXL motif. Furthermore, signaling by CLEC-2 is only partially dependent on the BLNK/SLP-76 family of adapter proteins in contrast to that of immunoreceptor tyrosine-based activation motif receptors. The C-type lectin receptor, Dectin-1, which contains a YXXL motif preceded by the same four amino acids as for CLEC-2 (DEDG), signals like CLEC-2 and also requires the two SH2 domains of Syk and is only partially dependent on the BLNK/SLP-76 family of adapters. In marked contrast, the C-type lectin receptor, DC-SIGN, which has a distinct series of amino acids preceding a single YXXL, signals independent of this motif. A mutational analysis of the DEDG sequence of CLEC-2 revealed that the glycine residue directly upstream of the YXXL tyrosine is important for CLEC-2 signaling. These results demonstrate that CLEC-2 and Dectin-1 signal through a single YXXL motif that requires the tandem SH2 domains of Syk but is only partially dependent on the SLP-76/BLNK family of adapters.

Received for publication, October 10, 2006 , and in revised form, February 16, 2007.

^* This work was supported in part by the British Heart Foundation, the Wellcome Trust, and in part by Ministry of Education, Culture, Sports, Science and Technology of Japan Grant 16790533. 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 Recipient of a British Heart Foundation Studentship.

² Supported an MRC New Investigator Award.

³ Supported by German Research Council Grant EB177/3-3 of SPP 1086.

⁴ British Heart Foundation Research Chair.

⁵ To whom correspondence should be addressed. Tel.: 44-121-415-8679; Fax: 44-121-415 8817; E-mail: a.c.pearce{at}bham.ac.uk.

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