These findings provide new insights into the influences and mechanisms involved in glucose metabolism of HDL. TIG3, which is also called retinoic acid receptor responder 3 and retinoid-inducible gene 1, is a one hundred sixty-four amino acid protein. TIG3 was originally identified as increased following treatment of cultured epidermal keratinocytes or psoriatic epidermis with the synthetic retinoid, Tazarotene. It is expressed at low levels in hyperproliferative epidermis and expression is restored by retinoid treatment. In retinoid-treated psoriatic epidermis, increased TIG3 expression is associated with restoration of normal differentiation. The association of increased TIG3 expression with normal epidermal phenotype suggests that TIG3 may act as a pro-differentiation regulator. To examine the mechanism of action, we studied TIG3 function in normal human keratinocytes. These studies show that TIG3 is present at vanishingly low levels in keratinocytes in monolayer culture, but is increased in differentiated raft cultures. Vector-mediated expression of TIG3 in keratinocytes results in reduced proliferation and increased cornified envelope formation, suggesting that TIG3 regulates keratinocyte differentiation. Ongoing studies show that TIG3 operates via several mechanisms, but a prominent mechanism of action is regulation of transglutaminase activity. Type I transglutaminase is a key enzyme in keratinocytes and other surface epithelia that is expressed in suprabasal differentiated cells. Transglutaminase catalyzes formation of M-lysine protein-protein crosslinks to assemble the cornified envelope, an essential component of the epidermal barrier. Our studies suggest that TIG3 colocalizes with TG1 leading to increased transglutaminase activity. Additional studies show that TIG3 reduces keratinocyte proliferation, but does not cause apoptosis. TIG3 consists of an amino terminal hydrophilic segment and a c-terminal membrane anchoring domain. Mutagenesis studies indicate that mutants lacking the c-terminal membrane-anchoring Oligomycin A domain are not active. In contrast, N-terminal truncation converts TIG3 into a protein that causes apoptosis in keratinocytes. TIG3 is expressed at reduced levels in skin tumors. Thus, a major goal of the present study is to characterize the impact of TIG3 expression in skin cancer cells. We show that restoring TIG3 expression reduces survival of epidermal squamous cell carcinoma cells via a mechanism that involves pericentrosomal TIG3 localization leading to altered microtubule organization and organelle distribution.