Kenneth Irvine Associate Professor Rutgers University Dept. of Molecular Biology and Biochemistry Waksman Institute Piscataway. NJ 08854 (732) 445-2332 FAX - 5735 irvine@waksman.rutgers.edu Visit Dr. Irvine's Homepage at Waksman Institute Search Pubmed for Dr. Irvine's Publications

Cell-signaling. pattern formation. growth control. developmental glycobiology

Research in my laboratory is directed toward understanding the regulation and coordination of tissue patterning, growth and morphogenesis during animal development. Much of our research takes advantage of the powerful genetic, molecular, and cellular techniques available in Drosophila melanogaster, which facilitate both gene discovery and the analysis of gene function.

Over the last several years, we have investigated the regulation and functions of the Notch signaling pathway. Notch is a receptor protein that mediates a wide range of cell fate decisions during animal development. In humans, aberrant Notch signaling has been linked to leukemia (TAN-1), and congenital syndromes associated with stroke and dementia (CADASIL), and liver, cardiovascular, and skeletal defects (Alagille, spondylocostal dysostosis). Notch and its ligands are modified by an unusual form of glycosylation, which is initiated by the attachment of fucose to Serines or Threonines within epidermal growth factor-like (EGF) repeats. We have studied the influence of this post-translational modification using a combination of Drosophila genetics, cell culture, and biochemistry.

Recently, we have begun investigating a new signaling pathway that links patterning and growth during development, the Fat signaling pathway. fat is a Drosophila gene that encodes a protocadherin which acts as a transmembrane receptor for this pathway. Fat signaling influences at least three processes during Drosophila development: it influences a form of cell polarity (planar cell polarity), it influences gene expression, and it influences growth. One product of our research has been the identification and characterization of the dachs gene as a critical downstream effector of Fat signaling. dachs encodes an unconventional myosin that preferentially localizes to the membrane of imaginal disc cells. A intriguing clue to the role of Dachs and the nature of Fat siganling has come from observation that Dachs protein localization is influenced by Fat signaling. Other studies have led to the identification of the Warts kinase and tumor suppressor as a downstream component of Fat signaling, and linked Fat signaling to Hippo signaling and the human tumor suppressor Merlin/NF2. We are continuing to characterize this pathway in Drosophila, and also beginning experiments to investigate Fat signaling in mammalian cells.

Selected Publications

Oh H, Reddy BV, Irvine KD. (2009) Phosphorylation-independent repression of Yorkie in Fat-Hippo signaling. Dev Biol. 335(1):188-97.

Mao Y, Kucuk B, Irvine KD. (2009) Drosophila lowfat, a novel modulator of Fat signaling. Development. 136(19):3223-33.

Feng Y, Irvine KD. (2009) Processing and phosphorylation of the Fat receptor. Proc Natl Acad Sci U S A. 106(29):11989-94.

Li GY, Zhang Y, Inouye M, Ikura M. (2009) Inhibitory mechanism of Escherichia coli RelE-RelB toxin-antitoxin module involves a helix displacement near an mRNA interferase active site.
J Biol Chem. 284(21):14628-36.

Oh H, Irvine KD. (2009)In vivo analysis of Yorkie phosphorylation sites. Oncogene. 28(17):1916-27.

Lin YR, Reddy BV, Irvine KD. (2008) Requirement for a core 1 galactosyltransferase in the Drosophila nervous system. Dev Dyn. 237(12):3703-14.

Reddy BV, Irvine KD. (2008) The Fat and Warts signaling pathways: new insights into their regulation, mechanism and conservation. Development. 135(17):2827-38.

Rogulja D, Rauskolb C, Irvine KD. (2008) Morphogen control of wing growth through the Fat signaling pathway. Dev Cell. 15(2):309-21.

Ishikawa HO, Takeuchi H, Haltiwanger RS, Irvine KD. (2008) Four-jointed is a Golgi kinase that phosphorylates a subset of cadherin domains. Science. 321(5887):401-4.

Oh H, Irvine KD. (2008) In vivo regulation of Yorkie phosphorylation and localization. Development. 135(6):1081-8.

Irvine KD. (2008) A notch sweeter. Cell. 132(2):177-9.

Okajima T, Reddy B, Matsuda T, Irvine KD. (2008) Contributions of chaperone and glycosyltransferase activities of O-fucosyltransferase 1 to Notch signaling. BMC Biol. 6:1.

Stolz A, Haines N, Pich A, Irvine KD, Hokke CH, Deelder AM, Gerardy-Schahn R, Wuhrer M, Bakker H. (2008) Distinct contributions of beta4GalNAcTA and beta4GalNAcTB to Drosophila glycosphingolipid biosynthesis. Glycoconj J. 25(2):167-75.

Feng Y, Irvine KD.(2007) Fat and expanded act in parallel to regulate growth through warts.
Proc Natl Acad Sci U S A. 104(51):20362-7.

Xu A, Haines N, Dlugosz M, Rana NA, Takeuchi H, Haltiwanger RS, Irvine KD. (2007) In vitro reconstitution of the modulation of Drosophila Notch-ligand binding by Fringe. J Biol Chem. 282(48):35153-62.

Mao, Y., Rauskolb, C., Cho, E., Hu, W.-L., Hayter, H., Minihan, G., Katz, F.N., and Irvine, K.D. (2006). Dachs, an unconventional myosin that functions downstream of Fat to regulate growth, affinity and gene expression in Drosophila. Development 133:2539-2551.

Cho, E., Feng, Y., Rauskolb, C., Maitra, S., Fehon, R., and Irvine, K.D. (2006). Delineation of a fat tumor suppressor pathway. Nature Genetics 38:1142-1150.

Major, R. and Irvine, K.D. (2006). Localization and requirement for Myosin II at the dorsal-ventral compartment boundary of the Drosophila wing. Dev. Dyn. 235:3051-3058.

Haines, N. and Irvine, K.D. (2005). Functional analysis of Drosophila N-Acetlygalactosaminyltransferases. Glycobiology 15:335-346.

Okajima, T., Xu, A., Lei, L. and Irvine, K.D. (2005). Chaperone activity of Protein O-fucosyltransferase 1 promotes notch receptor folding. Science 30:1599-1603.

Major, R. and Irvine, K.D. (2005). Influence of Notch on dorsal-ventral compartmentalization and actin organization in the Drosophila wing. Development 132:3823-3833.

Xu, A. Lei, L., and Irvine, K.D. (2005). Regions of Drosophila Notch that contribute to ligand binding and the modulatory influence of Fringe. J. Biol. Chem. 280:30158-30165.
Rogulja, D. and Irvine, K.D. 2005 Regulation of cell proliferation by a morphogen gradient. Cell 123:449-461.

Koles, K. Irvine, K. D., Panin, V. M. (2004). Functional characterization of Drosophila Sialyltransferase. J. Biol. Chem. 279:4346-57.

Cho, E. and Irvine, K.D. (2004). Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling. Development 131:4489-4500.

Li, Y. Lei, L., Irvine, K.D. and Baker, N.E. (2003). Notch activity in neural cells triggered by a mutant allele with altered glycosylation. Development 130:2829-2840.

Correia, T., Papayannopoulos, V., Panin, V., Woronoff, P., Jiang, J., Vogt T.F. and Irvine, K.D. (2003). Molecular genetic analysis of the glycosyltransferase Fringe in Drosophila. Proc. Nat. Acad. Sci. USA 100:6404-6409.

Okajima, T., Xu, A. and Irvine, K.D. (2003). Modulation of Notch-ligand binding by Protein O-fucosyltransferase 1 and Fringe. J. Biol. Chem. 278:42340-42345.

Haines, N. and Irvine, K.D. (2003). Glycosylation regulates the Notch signaling pathway. Nature Rev. Mole. Cell Biol. 4:786-797.

Lei, L., Xu, A., Panin, V. and Irvine, K. D. (2003). An O-fucose site in the ligand binding domain inhibits Notch activation. Development 130:6411-6421.