|
|
|
|||||||
|
|||||||||
Hofmann and Majerus 257 (11): 6461
Wilson et al. 259 (19): 11718
Wilson et al. 260 (2): 1046
J. Biol. Chem., Vol. 283, Issue 12, 7, March 21, 2008
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Classics
The Thrombin-induced Hydrolysis of Phosphatidylinositol: the Work of Philip W. Majerus
Identification and Properties of Two Distinct Phosphatidylinositol-specific Phospholipase C Enzymes from Sheep Seminal Vesicular Glands
(Hofmann, S. L., and Majerus, P. W. (1982) J. Biol. Chem. 257, 6461–6469)
Hydrolysis of Polyphosphoinositides by Purified Sheep Seminal Vesicle Phospholipase C Enzymes
(Wilson, D. B., Bross, T. E., Hofmann, S. L., and Majerus, P. W. (1984) J. Biol. Chem. 259, 11718–11724)
Phosphoinositide Interconversion in Thrombin-stimulated Human Platelets
(Wilson, D. B., Neufeld, E. J., and Majerus, P. W. (1985) J. Biol. Chem. 260, 1046–1051)
Philip W. Majerus received his B.S. from Notre Dame University in 1958 and his M.D. from the Washington University School of Medicine in 1961. He performed his internship and residency at Massachusetts General Hospital from 1961 to 1963 and was a research associate at the National Institutes of Health's National Heart Institute from 1963 to 1966. At the NIH, he worked with Journal of Biological Chemistry (JBC) Classic author P. Roy Vagelos on acyl carrier protein (1). Majerus then joined the Washington University Medical School faculty as an assistant professor and quickly achieved full professorships in medicine and biochemistry. He continues to do research at Washington University today and is currently co-director, along with JBC Classic author Stuart Kornfeld (2), of the Division of Hematology at Washington University.
|
When he first arrived at Washington University, Majerus continued to collaborate with Vagelos on acyl carrier protein. Soon, however, his interest turned to human platelets and their role in the clotting process. He was able to show that platelets were not merely a part of blood clots but that they also precipitated the clotting process. He was able to discover receptors on the surface of platelets that bound to clot-promoting factors, which activated prothrombin resulting in rapid and specific clotting in the area. Majerus is also credited with demonstrating the mechanism behind the clot-inhibiting effect of aspirin. He showed that low doses of aspirin modify cyclooxygenase, an enzyme that leads to the formation of thromboxane, which causes the constriction of blood vessels and aggregation of platelets.
This work on clotting led to Majerus' investigation of thrombin-induced hydrolysis of phosphatidylinositol in human platelets to produce water-soluble inositol phosphate messengers. This is the subject of the three JBC Classics reprinted here. Phosphatidylinositols are phospholipid components of the cell membrane. In response to extracellular signals, such as thrombin stimulation, these lipids are rapidly degraded by phosphatidylinositol-specific phospholipase C.
In the first JBC Classic, Majerus describes the isolation and preliminary characterization of two cytosolic phosphatidylinositol-specific phospholipase C enzymes from sheep seminal vesicles. The first enzyme was purified 5300-fold and had an estimated molecular weight of 65,000. The second phospholipase C was only partially purified. Antibodies directed against either enzyme did not cross-react with the other, indicating the enzymes were somewhat different in structure. The two enzymes were indistinguishable on the basis of reaction products, cellular location, or apparent Km for phosphatidylinositol but differed greatly in tissue distribution.
Majerus continued his investigation into the two enzymes in the second JBC Classic, comparing the ability of the purified enzymes to hydrolyze phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-diphosphate. He found that the two enzymes were able to hydrolyze all three phosphoinositides with the same affinity. From these experiments he concluded that "a single phospholipase C can account for the hydrolysis of all three phosphoinositides seen during agonist-induced stimulation of secretory cells. The cytoplasmic Ca+ concentration and phospholipid composition of the membrane, however, may influence the relative rate of hydrolysis of the three phosphoinositides."
In the final JBC Classic, Majerus looks at the pathway of phosphatidylinositol hydrolysis in thrombin-stimulated platelets. Based on previous studies, several groups had proposed that phosphatidylinositol is converted to phosphatidylinositol 4,5-diphosphate before hydrolysis rather than being directly hydrolyzed by phosphatidylinositol-specific phospholipase C. By incubating platelets with 32Pi and thereby labeling the phosphoinositides, Majerus was able to determine that there is little increase in conversion of phosphatidylinositol to phosphatidylinositol 4,5-diphosphate during thrombin stimulation. Thus, he concluded, the bulk of phosphatidylinositol breakdown that occurs in thrombin-stimulated platelets occurs via direct phospholipase C hydrolysis of phosphatidylinositol.
Majerus has received several awards and honors for his research including the Dameshek Prize for Research from the American Society of Hematology (1981), the Distinguished Career Award for Contributions to Hemostasis from the International Society for Thrombosis and Hemostasis (1985), the Kober Lecture Award from the Association of American Physicians (1991), the Robert J. and Claire Pasarow Foundation Award for Cardiovascular Research (1994), and the Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular/Metabolic Research (1998). He is a member of the National Academy of Sciences, the Institute of Medicine, and the American Academy of Arts and Sciences. Majerus served as President of both the American Society for Clinical Investigation (1981–1982) and the American Society of Hematology (1991). He has also undertaken many editorial responsibilities including serving on the editorial boards of the Journal of Lipid Research and the Journal of Biological Chemistry.
REFERENCES
- JBC Classics: Majerus, P. W., Alberts, A. W., and Vagelos, P. R. (1965) J. Biol. Chem. 240, 618–621; Majerus, P. W., Alberts, A. W., and Vagelos, P. R. (1965) J. Biol. Chem. 240, 4723–4726 (http://www.jbc.org/cgi/content/full/280/35/e32)
- JBC Classics: Tabas, I., Schlesinger, S., and Kornfeld, S. (1978) J. Biol. Chem. 253, 716–722; Li, E., Tabas, I., and Kornfeld, S. (1978) J. Biol. Chem. 253, 7762–7770; Kornfeld, S., Li, E., and Tabas, I. (1978) J. Biol. Chem. 253, 7771–7778 (http://www.jbc.org/cgi/content/full/282/11/e8)
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |