ring mutations in keratins may lead to genetic skin 
disease. 
Senior Investigator Edwin G. Krebs, M.D. (Uni- 
versity of Washington) and his colleagues are inter- 
ested in the molecular mechanisms involved in 
transmitting hormonal and grov^^h factor signals 
within the cell. One of the major mechanisms that 
nature has employed for this purpose is the revers- 
ible modification of existing cellular proteins by 
phosphorylation and dephosphorylation. These 
modification reactions are catalyzed by enzymes re- 
ferred to as protein kinases (phosphorylation 
steps) and protein phosphatases (dephosphoryla- 
tion steps). This laboratory is determining how the 
kinases and phosphatases are regulated by signals 
that impinge on the cell. By this means it may be- 
come possible to modify growth factor and hor- 
mone responses with drugs so that abnormalities in 
the signaling process can be corrected. 
Phosphorylation of rate-limiting proteins on ser- 
ine and threonine residues by protein kinases is a 
common cellular mechanism for modulating physi- 
ological processes. In the brain, calcium-dependent 
protein kinases are important in coordinating the 
changes in intracellular calcium that occur with 
neuronal activity. The laboratory of Investigator 
Thomas R. Soderling, Ph.D. (Vanderbilt University) 
has elucidated regulatory mechanisms for an abun- 
dant multifunctional calcium-dependent protein ki- 
nase of brain. These mechanisms may prove to be 
important for altering and prolonging synaptic 
events in the nervous system. 
The laboratory of Investigator Jackie D. Corbin, 
Ph.D. (Vanderbilt University) has studied the kinet- 
ics of the two cAMP sites of a fungal cAMP-depen- 
dent protein kinase and found them to be similar, 
but not identical, to those of the mammalian en- 
zyme. Mammalian cGMP-dependent protein kinase 
has cGMP sites that are structurally similar to the 
cAMP sites of cAMP-dependent protein kinase but 
differ by one amino acid. Either of these two iso- 
lated kinases can function as a single protein chain, 
even though the natural mammalian enzymes have 
more than one chain. Cellular cAMP-dependent 
protein kinase regulates its own activation by stim- 
ulating, through phosphorylation, an enzyme that 
degrades cAMP. 
In the laboratory of Investigator David L. Gar- 
bers, Ph.D. (Vanderbilt University) research on 
mechanisms of signaling in the spermatozoon re- 
sulted in the identification of the enzyme guanylate 
cyclase as a cell surface receptor. The cloning of the 
mRNA encoding this enzyme from mammalian tis- 
sues and the subsequent expression of guanylate 
cyclase in cultured cells demonstrated that it is a 
cell surface receptor for atrial natriuretic peptides. 
This enzyme receptor resembles the protein tyro- 
sine kinase receptors by virtue of its possessing a 
single transmembrane domain and a protein 
kinase-like domain. 
Eukaryotic cells respond to a diversity of physio- 
logical and pharmacological stimuli by molecular 
mechanisms that include transient rises in the con- 
centration of calcium inside the cell. Regardless of 
their source, these changes in calcium concentra- 
tion are transduced into a biological response 
through the interaction with calmodulin, a ubiqui- 
tous eukaryotic protein that has multiple biological 
roles. It is the goal of the research program in the 
laboratory of Investigator D. Martin Watterson, 
Ph.D. (Vanderbilt University) to understand the 
basic molecular mechanisms by which calmodulin 
is able to convert these small changes in calcium 
ion concentration into specific biological re- 
sponses. Interdisciplinary studies employing bio- 
physical methods and recombinant DNA technolo- 
gies have led to a general model of how calcium 
signals are converted by calmodulin into a biologi- 
cal response that has provided a rational basis for 
the design and production of new chimeric pro- 
teins and a mechanistic interpretation of how in- 
herited mutations of genes encoding calmodulin or 
a calmodulin-regulated enzyme might bring about 
selective nonlethal disorders. 
Calcium-dependent hormones act by binding to 
specific cell surface receptors and stimulating the 
breakdown of certain membrane lipids to generate 
signaling molecules that control the activities of en- 
zymes and other proteins. Work by Investigator 
John H. Exton, M.D., Ph.D. (Vanderbilt University) 
and his colleagues is directed toward identifying 
and chemically characterizing the enzymes that 
break down the lipids and the proteins that couple 
these enzymes to the receptors. Their work has led 
to the discovery of new mechanisms involving addi- 
tional lipids, enzymes, and signaling molecules that 
are involved in the actions of the hormones. The 
enzymes and coupling proteins that participate in 
the new signaling systems are being characterized, 
and their physiological roles are being defined. 
One emphasis of the research of Associate Inves- 
tigator Linda J. Van Eldik, Ph.D. (Vanderbilt Univer- 
sity) concerns the biological roles of the SlOO fam- 
ily of calcium-modulated proteins. During the past 
year, her laboratory has focused on the SlOOp pro- 
tein and its neurotrophic activity in the central ner- 
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