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Impaired Ca2+-Induced Tyrosine Phosphorylation and
Defective Lipid Scrambling in Erythrocytes From a Patient With Scott
Syndrome: A Study Using an Inhibitor for Scramblase That Mimics the
Defect in Scott Syndrome
David W.C. Dekkers,
Paul Comfurius,
Wim M.J. Vuist,
Jeffrey T. Billheimer,
Ira Dicker,
Harvey J. Weiss,
Robert F. A. Zwaal, and
Edouard M. Bevers
From the Department of Biochemistry, Cardiovascular Research
Institute Maastricht, Maastricht University, Maastricht, The
Netherlands; Dupont Merck Research Laboratory, Wilmington, DE; and the
Division of Hematology-Oncology, St. Luke's-Roosevelt Hospital Center,
New York, NY.
Scott syndrome is an hereditary bleeding disorder characterized by a
deficiency in platelet procoagulant activity. Unlike normal blood
cells, Scott platelets, as well as erythrocytes and lymphocytes, are
strongly impaired in their ability to scramble their membrane
phospholipids when challenged with Ca2+. In normal cells
this collapse of membrane asymmetry leads to surface exposure of
phosphatidylserine. Here we report that Scott erythrocytes show an
apparent defect in tyrosine phosphorylation on treatment with
Ca2+-ionophore. Diminished tyrosine phosphorylation was
also apparent in activated Scott platelets, but much less pronounced
than observed in red blood cells. On the other hand,
tyrosine phosphorylation profiles observed in Scott red blood cell
ghosts after sealing in the presence of adenosine triphosphate
(ATP) were indistinguishable from those obtained from
normal ghosts. Several observations argue in favor of a mechanism in
which tyrosine phosphorylation in red blood cells is facilitated by,
rather than required for scrambling of membrane lipids. Staurosporin
blocks tyrosine phosphorylation in normal red blood cells, but does not
inhibit the lipid scrambling process. White ghosts from normal
erythrocytes, resealed in the absence of ATP, exhibit
Ca2+-induced lipid scrambling without tyrosine
phosphorylation. A selective inhibitor of Ca2+-induced
lipid scrambling also showed an apparent inhibition of tyrosine
phosphorylation in ionophore-treated normal red blood cells, similar to
that observed in Scott erythrocytes. While this inhibitor also
suppressed Ca2+-induced lipid scrambling in ghosts that
were sealed in the presence of ATP, it did not inhibit tyrosine kinase
activity. We conclude that the apparent deficiency in tyrosine
phosphorylation in Scott cells is an epiphenomenon, possibly associated
with a defect in phospholipid scrambling, but not causal to this
defect.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2133-2138
© 1998 by The American Society of Hematology.
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