116 - P-Selectin

Summary

In 1984, two groups independently described monoclonal antibodies that bound to activated but not to resting platelets (1,2). The antibodies recognized a 140-kD platelet membrane glycoprotein. Immunocytochemical analysis revealed that the protein was concentrated in the membranes of α- granules in resting platelets (3,4). Thrombin and other agonists that induced fusion of α-granules with the plasma membrane caused the protein to redistribute to the platelet surface; this finding explained why the antibodies bound only to activated platelets. The protein was originally called granule membrane protein of 140 kDa (GMP-140) or platelet activation-dependent granule-to-external-membrane protein (PADGEM). Soon after, the same groups reported that endothelial cells (ECs) also expressed this protein (5–8). In resting endothelium, the protein was concentrated in membranes of Weibel-Palade bodies. Thrombin, histamine, and other agonists that induced fusion of Weibel-Palade bodies with the plasma membrane caused the protein to redistribute to the EC surface. Therefore, GMP-140/PADGEM was a glycoprotein that could be rapidly mobilized to the cell surface from storage granules by mediators generated during injury or infection (Figure 116.1). This suggested that the protein had important functions at vascular sites where platelets and/or ECs became activated.

In 1989, one of the groups reported the primary structure of GMP-140/PADGEM derived from protein sequencing and cDNA cloning (9). This analysis revealed a modular, type I membrane glycoprotein with an N-terminal domain similar to those in calcium (Ca²⁺)-dependent (C-type) lectins, followed by an epidermal growth factor (EGF)-like module, nine short consensus repeats related to those in complement regulatory and other proteins, a transmembrane domain, and a short cytoplasmic tail (Figure 116.2).