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© The Rockefeller University Press, 0021-9525/1998//1129 $5.00
The Journal of Cell Biology, Volume 143, Number 4, , 1998 1129-1141

Regular Articles

Role of P-Selectin Cytoplasmic Domain in Granular Targeting In Vivo and in Early Inflammatory Responses



Daqing W. Hartwell*,{ddagger}, Tanya N. Mayadas{ddagger},§, Gaëtan Berger*,{ddagger}, Paul S. Frenette*,||, Helen Rayburn, Richard O. Hynes,**, and Denisa D. Wagner*,{ddagger}

* Center for Blood Research, § Brigham and Women's Hospital, and {ddagger} 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

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 ({Delta}CT mice). The deletion did not affect the sorting of P-selectin into {alpha}-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 {Delta}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 {Delta}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.

Key Words: P-selectin • granular targeting • platelets • endothelium • cytoplasmic domain

Abbreviations used in this paper: {Delta}CT, P-selectin with a deleted cytoplasmic domain; CT, cytoplasmic domain; ES, embryonic stem; hGH, human growth hormone; LPS, lipopolysaccharide; PBS-T, PBS containing 0.1% Tween 20; PRP, platelet-rich plasma; vWF, von Willebrand factor.


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