P-Selectin

P-selectin is the largest of the known selectins at 140kDa. It contains nine consensus repeats (CR) and extends approximately 40 nm from the endothelial surface. Other names for P-selectin include CD62P, Granule Membrane Protein 140 (GMP-140), and Platelet Activation-Dependent Granule to External Membrane Protein (PADGEM). P-selectin is expressed in a-granules of activated platelets and granules of endothelial cells.

Within minutes of stimulation of the endothelial cells by inflammatory mediators such as histamine, thrombin, or phorbol esters, P-selectin is surface-expressed. Expression of P-selectin also occurs from the surgical trauma endured during preparation of the tissues for intravital microscopy. The expression is short-lived, reaching its peak after only ten minutes. Additional synthesis of P-selectin is brought about within two hours by cytokines such as interleukin-1 (IL-1) or tumor necrosis factor a (TNF-a). The primary ligand for P-selectin is PSGL-1 (P-selectin glycoprotein ligand-1) which is constitutively found on all leukocytes. Other ligands for P-selectin include CD24 and uncharacterized ligands. The transient interactions between P-selectin and PSGL-1 allow leukocytes to roll along the venular endothelium. Accordingly, P-selectin is largely responsible for the rolling phase of the leukocyte adhesion cascade. P-selectin can also mediate capture when L-selectin is not present.

Several experiments in mice have illustrated the pertinent role of P-selectin in leukocyte rolling. In mice deficient for P-selectin, trauma-induced rolling is absent immediately, but returns after 1-2 hours. In this case, the delayed rolling is L-selectin dependent, but the leukocytes roll much faster than in wild-type mice, suggesting that L-selectin cannot independently support rolling at typical in vivo velocities. On the other hand, in L-selectin deficient mice, P-selectin mediates most trauma-induced leukocyte rolling. Normal leukocyte rolling is seen for approximately 90 minutes, showing that P-selectin has the ability to capture leukocytes from the bloodstream and start them rolling along the endothelium even without the presence of L-selectin.

In TNF-a -stimulated venules, P-selectin and E-selectin tend to have overlapping functions. In mice deficient for P-selectin, it is necessary to block E-selectin function to significantly reduce rolling, and in E-selectin knockouts, an antibody against P-selectin must be introduced to reduce rolling. Correspondingly, no leukocyte rolling is observed in E-selectin/P-selectin double deficient mice treated with TNF-a. Although P- and E-selectin seem to have redundant functions, observations of rolling flux fraction and rolling velocity indicate that P-selectin is responsible for early rolling while E-selectin allows slow rolling and more adhesion.

Representative 3-D Structure of P-Selectin: only the EGF domain of P-selectin. Also available is a theoretical 3-D model of P-selectin (the C-type lectin domain, and residues 1-120). These 3-D structures are viewed using RasMol. Left-clicking on the molecule allows change in orientation, and right-clicking on the molecule gives options for different display modes.

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