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J. Cell Biol.,
Volume 143, Number 4, November 16, 1998 1129-1141
§
* Center for Blood Research, § Brigham and Women's Hospital, and P-selectin is an adhesion receptor for leukocytes expressed on activated platelets and endothelial
cells. The cytoplasmic domain of P-selectin was shown
in vitro to contain signals required for both the sorting
of this protein into storage granules and its internalization from the plasma membrane. To evaluate in vivo the role of the regulated secretion of P-selectin, we
have generated a mouse that expresses P-selectin lacking the cytoplasmic domain ( Department of Pathology and Department of Medicine,
Harvard Medical School, Boston, Massachusetts 02115; and ** Howard Hughes Medical Institute and ¶ Center for Cancer
Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
CT mice). The deletion
did not affect the sorting of P-selectin into 
-granules
of platelets but severely compromised the storage of
P-selectin in endothelial cells. Unstored P-selectin was
proteolytically shed from the plasma membrane, resulting in increased levels of soluble P-selectin in the
plasma. The CT-P-selectin appeared capable of mediating cell adhesion as it supported leukocyte rolling in
the mutant mice. However, a secretagogue failed to upregulate leukocyte rolling in the CT mice, indicating
an absence of a releasable storage pool of P-selectin in
the endothelium. Furthermore, the neutrophil influx
into the inflamed peritoneum was only 30% of the wild-type level 2 h after stimulation. Our results suggest that
different sorting mechanisms for P-selectin are used in
platelets and endothelial cells and that the storage pool
of P-selectin in endothelial cells is functionally important during early stages of inflammation.
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