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
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.
Panin, V.M., Shao, L., Lei, L., Moloney, D.J.,
Irvine, K.D., and Haltiwanger, R.S. (2002). Notch ligands are substrates for
Protein O-fucosyltransferase-1 and Fringe. J. Biol. Chem. 277: 29945-29952.
Grammont, M. and Irvine, K.D. (2002). Organizer activity of the polar cells
during Drosophila oogenesis. Development 129:5131-5140.
Nakamura, Y., Haines, N., Chen, J., Okajima, T., Furukawa, K., Urano, T.,
Stanley, P., Irvine, K.D., and Furukawa, K. (2002). Identification of a
Drosophila gene encoding xylosylprotein ß4-galactosyltransferase that is
essential for the synthesis of glycosaminoglycans and for morphogenesis. J.
Biol. Chem. 277:46280-46288.
Okajima, T. and Irvine, K.D. (2002). Regulation of Notch signaling by
O-linked fucose. Cell 111: 893-904.
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