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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3008-3009.
The sticking pointNEW YORK BLOOD CENTER
A signaling pathway involving activation of the GTPase Rap1 may play a role in increased adhesiveness of sickle red cells to the extracellular matrix protein laminin.
In this issue of Blood, Murphy and colleagues answer in the affirmative. They offer evidence that signaling events do indeed act in sickle red cell adhesion. They have identified as a player receptor-associated protein 1 (Rap1), a small guanosine triphosphatase (GTPase) known to promote integrin-mediated adhesion in various cells, by modulating the attachment of sickle red cells to laminin. As this adhesive interaction is mediated by the immunoglobulin (Ig) superfamily adhesion receptor basal cell adhesion molecule/Lutheran (BCAM-LU) and not by an integrin, these findings provide additional support for a role for Rap1 in regulating integrin-independent adhesive interactions. There is a general perception that a red cell is a "dead" cell with no active functions. Not so! Recent studies have revealed that the red cell membrane is a dynamic structure in which skeletal protein interactions and association of glycolytic enzymes with membrane proteins are highly regulated, that ligand binding to the transmembrane protein glycophorin A induces inward signaling, and that adhesion events are governed by phosphorylation. The findings of the present study point yet again to the active regulation of red cell function. What are the implications of the new observations for our understanding of sickle cell biology? A puzzling aspect of various cell adhesion studies to date has been their failure to explain why sickle cells are more adhesive than normal cells and why the adhesive phenotype varies from patient to patient. Could differences in cell signaling activation pathways account for the observed differences? Do adhesive interactions mediated by integrins employ the same signaling pathways as those dependent on other adhesion molecules on red cells? The new findings will perhaps point the way to new approaches for tackling these difficult issues.
The most important unresolved question in sickle cell disease is the extent of the link between the increased adhesivity of sickle cells and the pathophysiology of the disease. While the numbers of adhesive receptors and ligands engaged in the process of sickle cell adhesion in vitro keep growing, there have still been no systematic attempts to define the relative importance of their many interactions to in vivo flow abnormalities under physiologically relevant conditions. Without serious efforts to fill this major gap in our understanding there will be no way to translate the outcomes of the various elegant fundamental studies, such as the present, into a proper grasp of the pathophysiology of the disease and the eventual development of new therapeutic strategies. References
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