Associate Professor, Baylor College of Medicine
M.D., Tehran University of Medical Sciences, Tehran, Iran, 1994
Postdoc, University of Ottawa, Canada, 1999-2000
Postdoc, Baylor College of Medicine, 2000-06
Developmental glycobiology; Notch signaling
Glycosylation is the most common post-translational modification of extracellular proteins and plays major roles in various aspects of cellular and organismal biology. However, the specific role of various carbohydrate residues in modifying the behavior of proteins and consequently regulating cellular processes are largely unknown. The long-term goal of our research is to understand the contribution of carbohydrates to the regulation of animal development. Our current work is focused on the regulation of the Notch signaling pathway by “protein O-glucosylation”. A number of secreted and transmembrane proteins, including several coagulation factors and Notch proteins, harbor an O-linked glucose residue on epidermal growth factor-like (EGF) repeats with a C1-X-S-X-P-C2 motif. The O-glucose can be extended by the addition of one or two xylose residues. Several years ago, we identified the protein O-glucosyltransferase Rumi in Drosophila and showed that loss of Rumi results in temperature-dependent loss of Notch signaling in flies. Building on this initial discovery, the goal of our research is to address the following questions:
- How do O-glucose residues and their extended forms regulate Drosophila Notch signaling?
Using a combination of genetic engineering, cell biology and biochemistry, we aim to understand how O-linked glucose help maintain wild-type levels of Notch signaling despite variations in the temperature at which the flies are raised. The recent identification of the enzymes responsible for the addition of xylose to O-linked glucose has paved the way for functional analysis of the role of xylose residues in Notch signaling. Using a combination of fly genetics, cell culture and biochemical experiments, we are examining whether xylose residues play a regulatory role in Notch signaling.
- What is the role of O-linked glucosylation in the regulation of mammalian Notch signaling?
Drosophila Rumi is the first protein O-glucosyltransferase (Poglut) enzyme identified in animals. Moreover, the extracellular domains of the mammalian Notch proteins have a large number of O-glucosylation motifs with an evolutionarily conserved distribution. We therefore asked whether Rumi regulates mammalian Notch signaling, and found that mouse Rumi (official name: Poglut1) is involved in the regulation of the Notch signaling and embryonic development. We are currently using mouse genetics and cell culture experiments to examine the molecular basis for the sensitivity of the mammalian Notch signaling to the level of Rumi.
- Does Rumi play a regulatory role in contexts other than the Notch pathway?
Although Notch receptors harbor a large number of Rumi target motifs, a number of other transmembrane and secreted proteins also contain EGF repeats with a C1-X-S-X-P-C2 motif and might therefore be glucosylated by Rumi. Part of our efforts is devoted to the identification of other biologically-relevant targets of Rumi.
The Notch signaling pathway plays key roles in animal development and in stem cell biology. Moreover, mutations in the components of this pathway cause a variety of human diseases, including cancer, developmental disorders affecting heart, liver, skeleton and other organ systems, and adult-onset dementia. Therefore, providing insight into the role of carbohydrates in regulating the Notch signaling pathway could potentially contribute to our understanding of the pathogenesis of Notch-related diseases and could provide new therapeutic targets in these diseases.
Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122:633-644.
Jafar-Nejad H, Tien AC, Acar M, Bellen HJ (2006) Senseless and Daughterless confer neuronal identity to epithelial cells in the Drosophila wing margin. Development 133:1683-1692.
Acar M*, Jafar-Nejad H*, Giagtzoglou N, Yallampalli S, David G, He Y, Delidakis C, Bellen HJ (2006) Senseless physically interacts with proneural proteins and functions as a transcriptional co-activator. Development 133:1979-1989. (*equal contribution)
Simcox AA, Austin CL, Jacobsen TL, Jafar-Nejad H (2008) Drosophila embryonic ‘fibroblasts’: extending mutant analysis in vitro. Fly 2:306-309.
Acar M*, Jafar-Nejad H*, Takeuchi H*, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ (2008) Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132:247-258. (*equal contribution)
Jafar-Nejad H, Leonardi J, Fernandez-Valdivia R (2010) Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology 20:931-949.
Lee TV, Takeuchi H, Jafar-Nejad H (2010) Regulation of Notch signaling via O-glucosylation insights from Drosophila studies. Methods in Enzymology 480C:375-398.
Fernandez-Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, Jafar-Nejad H (2011) Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi. Development 138:1925-1934.
Leonardi J, Fernandez-Valdivia R, Li YD, Simcox AA, Jafar-Nejad H (2011) Multiple O-glucosylation sites on Notch function as a buffer against temperature-dependent loss of signaling. Development 138:3569-3578.
Takeuchi H, Fernández-Valdivia RC, Caswell DS, Nita-Lazar A, Rana NA, Garner TP, Weldeghiorghis TK, Macnaughtan MA, Jafar-Nejad H, Haltiwanger RS (2011) Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. Proceedings of the National Academy of Sciences USA 108:16600-16605.
Hamed Jafar-Nejad, M.D.
Department of Molecular & Human Genetics
Baylor College of Medicine
One Baylor Plaza, Room 919E
Houston, Texas 77030, U.S.A.
Tel: (713) 798-6159