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James A. Shayman, M.D.

Research Summary:

Sphingolipids are ubiquitous and multifunctional cell membrane compo­nents that serve as cell surface receptors, agonists and intracellular second messengers. They appear to mediate a variety of cellular responses including growth and differentiation, and stress responses. Because of the large number of Sphingolipids metabolites and wide potential range of effects, understanding the role of specific sphingolipids has proven challenging to investigators. Dr. Shayman’s laboratory has recently developed ceramide homologues which inhibit specifically and potently selective pathways of ceramide metabolism. These ceramide homologues have proven useful in at least two respects. First, they have provided insight into the role of sphingolipids as mediators of particular pathophysiologic processes including diabetic renal hypertrophy and the heat shock response. Second, these homologues have provided insights into the role of ceramides in cell signaling phenomena including gene transcription and cell cycle progression. His laboratory is now evaluating the use of these inhibitors as potential therapeutic agents for glycolipid storage disorders.

Link to PubMed Citations

Selected Publications:

Shayman, J.A. Glucosylceramide and galactosylceramide synthase. In Sphingolipid Biology, Y. Hirabayashi, J. Inokuchi and A.H. Merrill (eds.) Springer-Verlag, Tokyo (in press).

Shayman, J.A. The biochemistry and cellular biology of sphingolipids and glucosylceramide. Gaucher Disease. Anthony Futerman and Ari Zimran (eds.) CRC Press (in press).

Shen, Y, Bodary, PF, Vargas, FB, Homeister, JW, Gordon, D, Ostenso, KA, Shayman, JA, and Eitzman, DT. Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation. Stroke 37: 1106-8, 2006.

Pi, X, Tan, SY, Hayes, M, Xiao, L, Shayman, JA, Ling, S, Holoshitz, J. Sphingosine kinase 1-mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells. Arthritis Rheum. 54: 754-64, 2006.

Shayman, JA. Thinking about rare kidney diseases. J. Am. Soc. Nephrol. 17: 15-6, 2006.

Hiraoka, M, Abe, A, and Shayman, JA. Structure and function of lysosomal phospholipase A2: identification of the catalytic triad and the role of cysteine residues. J. Lipid. Res. 11: 2441-7, 2005.

Shu, L, Murphy, HS, Cooling, L, and Shayman, JA. An in vitro model of Fabry disease. J. Am. Soc. Nephrol. 16: 2636-45, 2005.

Hinkovska-Galcheva, V, Boxer, LA, Kindzelskii, A, Hiraoka, M, Abe, A, Goparju, S, Spiegel, S, Petty, HR, and Shayman, JA. Ceramide-1-phosphate: a mediator of phagocytosis. J. Biol. Chem. 280: 26612-21, 2005.

Mansfield , PJ, Hinkovska-Galcheva, Borofsky , MS , Shayman, JA, and Boxer, LA. Phagocytic signaling molecules in lipid rafts of COS-1 cells transfected with Fc-gamma-RIIA. Biochem. Biophys. Res. Comm. 331: 132-8, 2005.

Bodary, PF, Shen, Y, Vargas, FB, Bi, X, Ostenso, KA, Gu, S, Shayman, JA, and Eitzman, DT. Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. Circulation 111: 629-32, 2005.

Abe, A, Hiraoka, M, Wild, S, Wilcoxen, S, Paine, R 3rd, and Shayman, JA. Lysosomal phospholipase A2 is selectively expressed in alveolar macrophages. J Biol Chem 279: 42605-11, 2004.

Akira Abe and James A. Shayman. Sphingolipid Catabolism. Encyclopedia of Biochemistry edited by William J. Lennarz and M. Daniel Lane Elsevier, Academic Press. (2004)

Abe, A, Poucher, H, Hiraoka, M, and Shayman, JA. Induction of lysosomal phospholipase A2 through the retinoid X receptor in THP-1 cells. J. Lipid Res. 45:667-73, 2004.

Mansfield, PJ, Carey, SS, Shayman, JA, and Boxer, LA. Ceramide inhibition of phospholipase D through inhibition of RhoA translocation in a cell-free system. Blood 103: 2363-8, 2004.

Shayman, JA, Abe, A, and Hiraoka, M. A turn in the road: how studies on the pharmacology of glucosylceramide synthase inhibitiors led to the identification of a lysosomal phospholipase A2 with ceramide transacylase activity. Glycoconj. J. 20: 25-32, 2003.

Shu, L, and Shayman, JA. Src kinase mediates the regulation of phospholipase C-gamma activity by glycosphingolipids. J Biol Chem 278(33):31419-25, 2003.

Eitzman, DT, Bodary, PF, Shen, Y, Khairallah, CG, Wild, SR, Abe, A, Shaffer-Harman, J, Shayman, JA. Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. Journal American Society of Nephrology 14: 298-302, 2003.

Hinkovska-Galcheva, V, Mansfield, PJ, Schreiber, A, Boxer, LA, and Shayman, JA. Enhanced phagocytosis through inhibition of denovo ceramide synthesis Journal of Biological Chemistry 278: 974-82, 2003.

Levery, SB, Momany, M, Lindsey, R, Toledo, MS, Shayman, JA, et al. Disruption of the glucosylceramide biosynthetic pathway in Aspergillusnidulans and Aspergillusfumigatus by inhibitors of UDP-Glc:ceramide glucosyltransferase strongly affects spore germination, cell cycle, and hyphal growth. FEBS Lett, 525: 59-64, 2002.

Shu, L, Lee, L, Shayman, JA. Regulation of phospholipase C-γ by glycosphingolipids. J Biol Chem, 277: 18447-18453, 2002.

Mansfield, PJ, Hinkovska-Galcheva V, Carey SS, Shayman JA, Boxer LA. Regulation of polymorphonuclear leukocyte degranulation through inhibition of phospholipase D. Blood 99: 1434-41, 2002.

Hiraoka M, Abe A, Shayman JA. Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase. J Biol Chem 277: 10090-10099, 2002.

Shayman JA. Kidney International. Perspectives in basic science: Sphingolipids. Kidney Intern. 58:11-26, 2000.

Abe A, Gregory S, Lihsueh L, Shayman JA. The use of sulfobutyl ether β-cyclodextrin as a vehicle for PDMP related glucosylceramide synthase inhibitors. Analytical Biochemistry. 287:344-347, 2000.

Abe, A, Gregory, S, Lee, L, Killen, PD, Kulkarni, A, Brady, RO, and Shayman, JA. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest, 11:105;1563-1571, 2000.

Mansfield, PJ, Shayman, JA, and Boxer, LA. Regulation of polymorphonuclear leukocyte phagocytosis by myosin light chain kinase following activation of MAP kinase. Blood 95:2407-2412, 2000.

Abe, A, Arend LJ, Lee, L, Lingwood, C, Brady RO, and Shayman, JA. Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase. Kidney Intern. 57:446-454, 2000.

Shu, L, Lee, L, Chang, Y, Holzman, LB, Edwards, CA, Shelden, E, Shayman, JA. Caveolar structure and protein sorting are maintained in NIH 3T3 cells independent of glycosphingolipid depletion. Arch. Biochem. Biophys. 373: 83-90, 2000.

Shayman JA, Abe A. Glucosylceramide synthase: assay and properties. Methods in Enzymol. 311: 42-9, 2000.

Shayman JA, Lee L, Abe A, Shu L. Inhibitors of glucosylceramide synthase. Methods in Enzymol. 311: 373-87, 2000.

Shayman JA, Abe A. 1-0-Acylceramide Synthase. Methods in Enzymol. 311: 105-117, 2000.


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