Jerry Kaplan
Professor of Pathology
B.S. State University of New York, Stony Brook
Ph.D. Purdue University
Diane McVey Ward
Research Assistant Professor of Pathology
B.S. Brigham Young University
Ph.D. University of Utah
Research
Our research focuses on two major areas. First, we are interested in iron metabolism. Iron is an element required by virtually all organisms. The facile ability of iron to gain and loose electrons renders this metal an essential cofactor in redox reactions. Organisms as disparate as prokaryotes and mammals have developed a variety of mechanisms to obtain iron and regulate its storage and utilization. We utilize yeast as a model system to study iron metabolism because of the relative ease of genetic manipulation. We have utilized a variety of genetic screens to identify yeast genes required for iron transport across the plasma membrane for iron storage in the yeast vacuole. We have also identified molecules that respond to both high and low iron and regulate the transcription of iron transporters. Our studies in yeast have led to the identification of both plant and mammalian iron transporters.
We have also identified the mechanisms underlying both the regulation and malregulation of mammalian iron-linked disorders. We determined that entry of iron from cells into plasma is dependent upon the interaction of the iron exporter ferroportin with the peptide hormone hepcidin. Hepcidin is synthesized by the liver in response to inflammation and iron stores and is a negative regulator of plasma iron. We determined that hepcidin binds to ferroportin inducing its internalization and degradation. Mammalian iron overload disease is the result of either inadequate hepcidin production or mutations in ferroportin that lead to hepcidin resistance. Our current studies have identified the mechanism of hepcidin-mediated ferroportin internalization and degradation.
Our second area of research is the study of membrane trafficking. We are interested in identifying molecules that regulate the fusion and fission of endocytic vesicles. Many human diseases result from alterations vesicle trafficking and delivery to the lysosomes. One such disease is Chediak-Higashi syndrome in which lysosomes are abnormally large. We have identified the gene responsible for this disorder and have ongoing studies to identify the biochemical defect responsible for the enlargement of lysosomes.
References
1. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, Ganz T, Musci G, Kaplan J (2007) The Molecular Mechanism of Hepcidin-Mediated Ferroportin Downregulation. Mol. Biol. Cell., In Press
2. Zohn IE, De Domenico I, Pollock A, Ward DM, Goodman JF, Liang X, Sanchez AJ, Niswander L, Kaplan J (2007) The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood, In Press
3. De Domenico I, Ward DM, Musci G, Kaplan J (2007) Evidence for the multimeric structure of ferroportin. Blood 109:2205-9
4. Kim SA, Punshon T, Lanzirotti A, Li L, Alonso JM, Ecker JR, Kaplan J, Guerinot ML (2006) Localization of iron in Arabidopsis seed requires the vacuolar membrane transporter VIT1. Science 314:1295-8
5. De Domenico I, Vaughn MB, Li L, Bagley D, Musci G, Ward DM, Kaplan J (2006) Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J. 25:5396-404
6. Davis-Kaplan SR, Compton MA, Flannery AR, Ward DM, Kaplan J, Stevens TH, Graham LA (2006) PKR1 encodes an assembly factor for the yeast V-type ATPase. J. Biol. Chem. 281:32025-35
7. Runkel F, Bussow H, Seburn KL, Cox GA, Ward DM, Kaplan J, Franz T (2006) Grey, a novel mutation in the murine Lyst gene causes the beige phenotype by skipping of exon 25. Mamm Genome 3:203-10
8. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AM, Wingert RA, Traver D, Trede NS, Barut BA, Zhou Y, Minet E, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI Paw BH (2006) Mitoferrin is essential for erythroid iron assimilation. Nature 440:96-100
9. Crisp RJ, Adkins EM, Kimmel E, Kaplan J (2006) Recruitment of Tup1p and Cti6p regulates heme-deficient expression of Aft1p target genes. EMBO. J 25:512-21
10. Kumanovics A, Poruk KE, Osborn KA, Ward DM, Kaplan J (2006) YKE4 (YIL023C) encodes a bidirectional zinc transporter in the endoplasmic reticulum of Saccharomyces cerevisiae. J. Biol. Chem. 281:22566-74
11. Paw BH, Shaw GC, Kingsley P, Palis J, Schubert H, Chen O, Kaplan J, Zon LI (2005) Tubingen 2000 Screen Consortium. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 436:1035-39
12. Felice MR, De Domenico I, Li L, Ward DM, Bartok B, Musci G, Kaplan J (2005) Post-transcriptional regulation of the yeast high affinity iron transport system. J. Biol. Chem. 280:22181-90
13. Ward DM, Vaughn MB, Shiflett SL, White PL, Pollock AL, Hill J, Schnegelberger R, Sundquist WI, Kaplan J (2005) The role of LIP5 and CHMP5 in multivesicular body formation and HIV-1 budding in mammalian cells. J Biol Chem. 280:10548-10555
14. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090-2093
