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Cutting Edge: Internalization of Transduced E-Selectin by Cultured Human Endothelial Cells: Comparison of Dermal Microvascular and Umbilical Vein Cells and Identification of a Phosphoserine-Type Di-leucine Motif ¹

Martin S. Kluger^2,*,, Stephen L. Shiao^*, Alfred L. M. Bothwell^*, and Jordan S. Pober^*,,,

^* Interdepartmental Program in Vascular Biology and Transplantation, Departments of Dermatology and Pathology, and Section of Immunology, Yale University School of Medicine, New Haven, CT 06536

Persistent E-selectin expression on human dermal microvascular endothelial cells (HDMEC), believed to mediate skin-specific T cell homing, results from a slow rate of surface protein internalization after cytokine induction. Following transduction of unactivated HDMEC with E-selectin cDNA, the rate of internalization was largely independent of increasing levels of surface protein expression, leading to prolonged t_1/2 values of over 4 h, comparable to that observed following cytokine induction. In HUVEC, the rate of internalization increased with surface expression level, leading to an essentially constant t_1/2 of under 2 h. Thus, the internalization process rather than cytokine responsiveness or E-selectin structure underlies the difference in endothelial cell behavior. Mutational analysis of the cytoplasmic region demonstrated a role for a di-leucine-type motif involving I588 and L589 but not for a putative tyrosine-type motif. Control of E-selectin surface expression appears to be phosphoserine dependent, since alanine but not aspartic acid substitution for S581 slows E-selectin internalization.

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