dimer formation to determine whether p34 is re- 
sponsible for desensitizing the EGF receptor. In ad- 
dition, studies are in progress to determine the ef- 
fect on EGF receptor function of altering the site of 
p34cdc2 phosphorylation. 
Dr. Pike is also Associate Professor of Biochem- 
istry and Molecular Biophysics at Washington 
University School of Medicine, St. Louis. 
Article 
Spizz, G., and Pike, L.J. 1992. Growth factors pro- 
mote inositol uptake in BC3H1 cells. Biochem 
Biophys Res Commun 182:1008-1015. 
MOLECULAR AND CELL BIOLOGY OF BLOOD COAGULATION 
J. Evan Sadler, M.D., Ph.D., Associate Investigator 
Dr. Sadler is interested in the structure, function, 
and regulation of proteins that are required for he- 
mostasis. In particular, he studies how cells that 
contact the blood maintain a balance between stimu- 
lating and inhibiting blood coagulation and how 
this balance is disrupted in human diseases. Dr. 
Sadler concentrates on two areas: 1 ) von Willebrand 
factor and von Willebrand disease and 2) the regula- 
tion of blood coagulation by endothelial cells. 
Molecular Biology of von Willebrand 
Factor and von Willebrand Disease 
von Willebrand factor (vWF) is a multimeric 
plasma protein that is synthesized by vascular endo- 
thelial cells. It is required for platelet adhesion to 
sites of injury and for normal survival of factor VIII 
in the circulation, von Willebrand disease (vWD) is 
the most common inherited bleeding disorder of 
humans and is phenotypically heterogeneous. 
vWD is divided into three categories. Type I, the 
most common form, is characterized by partial 
quantitative deficiency of vWF and is inherited as a 
dominant disorder. Type II is characterized by quali- 
tative deficiency; many subtypes are recognized that 
differ in mode of inheritance, clinical severity, and 
properties of the dysfunctional protein. Type III is 
an autosomal-recessive, severe disease with virtual 
absence of vWF. Knowledge of the molecular de- 
fects in vWD will illuminate structure-function rela- 
tionships of vWF and may lead to improved therapy. 
von Willebrand disease type IIA. vWF mediates 
platelet adhesion by binding to platelet glycopro- 
tein (GP) lb. vWD type IL\ is characterized by de- 
creased binding to GPIb and by the absence from 
plasma of high-molecular-weight vWF multimers. 
Mutations in this subtype cluster within the A2 do- 
main of the mature vWF subunit that is encoded 
by exon 28. Dr. Sadler and his colleagues found 
three missense mutations in this exon that result 
in the amino acid substitutions Arg(834) -> Trp, 
Gly(742) Glu, and Ser(743) ^ Leu. The first 
mutation occurred independently in three unre- 
lated families; each of the latter mutations was 
found in one family. The high frequency of identical 
independent mutations suggests that precise diag- 
nosis of vWD type ILA may be possible in a majority 
of patients by using simple DNA screening assays. 
von Willebrand disease Normandy. In vWD Nor- 
mandy, a rare type II variant, the mutant vWF ap- 
pears structurally and functionally normal except 
that it does not bind to blood coagulation factor 
VIII. This interaction is required for normal survival 
of factor VIII in the circulation; consequently, vWD 
Normandy can present as apparent hemophilia Abut 
with autosomal-recessive rather than X chromo- 
some-linked inheritance. Missense mutations in or 
near the factor Vlll-binding site on vWF have been 
identified in several families with vWD Normandy. 
Patients from one family were found to be homozy- 
gous for a C T transition in a CG dinucleotide, 
converting Arg(53) to Trp. The corresponding re- 
combinant mutant vWF had the same defect in factor 
VIII binding as the patients' plasma vWF, confirm- 
ing that the Arg(53) ^ Trp mutation causes vWD 
Normandy. These results suggest that the disulfide 
loop containing Arg(53) may bind factor VIII; this 
region of vWF was not previously known to be in- 
volved in this interaction. 
Regulation of Blood Coagulation 
The vascular endothelium normally inhibits 
blood-clotting reactions. The anticoagulant proper- 
ties of endothelium are due in part to the expression 
of thrombomodulin, a cell surface receptor that 
binds the serine protease thrombin and alters its 
substrate specificity. 
Thrombin is a multifunctional protease that has 
both procoagulant and anticoagulant activities. As a 
procoagulant enzyme, thrombin clots fibrinogen, 
activates clotting factors V and VIII, and activates 
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