Layilin, a ~55-kDa lectin, is a widely expressed integral membrane hyaluronan receptor, originally identified as a binding partner of talin located in membrane ruffles. It is recruited to membrane ruffles in cells induced to migrate in in vitro wounding experiments and in peripheral ruffles in spreading cells. Layilin is a transmembrane C-type lectin (Fig. 40.1) and binds specifically to hyaluronan (HA) but not to other tested glycosaminoglycans and belongs to group VIII of CTLDs. The other member of this group is chondrolectin. Layilin’s ability to bind hyaluronan reveals an interesting parallel between layilin and CD44, because both can bind to cytoskeleton-membrane linker proteins through their cytoplasmic domains and to hyaluronan through their extracellular domains. This parallelism suggests a role for layilin in cell adhesion and motility (Banerji et al. 1999; Bono et al. 2001). There is no sequence homology with known hyaluronan receptors, including CD44, RHAMM (receptor for HA-mediated motility), or LYVE-1 (lymphatic vessel endothelial HA receptor-1). Thus, by binding to HA, layilin may facilitate cell migration by mediating early interactions between spreading cells and the extracellular matrix (ECM). Since, hyaluronan is involved in invasion of a variety of tumor cells and layilin was detected in the human lung cell line A549, layilin might play crucial roles in lymphatic metastasis of lung carcinoma. Suppression of layilin expression by iRNA significantly increased survival of tumor-bearing mice. The suppression of layilin expression might be a promising strategy for treatment of human lung carcinoma (Chen et al. 2008).