This research focuses on a recently identified intercellular signaling pathway, the Fat pathway. The normal development and physiology of all animals, including humans, depends upon a relatively small number of highly conserved signaling pathways. The proposed studies will take advantage of powerful genetic and molecular technologies available in Drosophila, the organism in which this pathway was discovered. Available evidence suggests that Fat signaling plays a unique role in Drosophila by interpreting gradients of positional information to regulate tissue growth and polarity. Components of the pathway are conserved in humans, and are expressed in many different organ systems. Some components have already been implicated in tumor formation, both in Drosophila and in humans. This proposal has two long range goals. One is to better define the biological functions and regulation of the Fat pathway, which will be important to understanding its importance in normal development and physiology. The second is to understand how the pathway works at a molecular level. This could ultimately form a basis for manipulating the pathway to influence disease states. The first specific aim is to determine how gradients of Fat regulators influence Fat activity. These experiments will provide new insights into the regulation of Fat in developing tissues, and will test our working model for Fat pathway regulation, which explains how Fat signaling could link morphogen gradients to tissue growth.
The second aim i s to define the molecular basis for intracellular signaling from Fat to Warts. The experiments proposed in this aim will explore the """"""""logic"""""""" of the Fat signaling pathway, by using functional (genetic) and physical (biochemical) approaches to explore the activities and relationships among known Fat pathway components.
The third aim i s to enhance our understanding of Fat signaling by identifying new pathway components, using both genetic and biochemical screens. Together these experiments will provide a framework for understanding the mechanistic basis for Fat signaling.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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Rutgers University
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New Brunswick
United States
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Misra, Jyoti R; Irvine, Kenneth D (2018) The Hippo Signaling Network and Its Biological Functions. Annu Rev Genet 52:65-87
Pan, Yuanwang; Al├ęgot, Herve; Rauskolb, Cordelia et al. (2018) The dynamics of Hippo signaling during Drosophila wing development. Development 145:
Irvine, Kenneth D; Shraiman, Boris I (2017) Mechanical control of growth: ideas, facts and challenges. Development 144:4238-4248
Bilder, David; Irvine, Kenneth D (2017) Taking Stock of the Drosophila Research Ecosystem. Genetics 206:1227-1236
Pan, Yuanwang; Heemskerk, Idse; Ibar, Consuelo et al. (2016) Differential growth triggers mechanical feedback that elevates Hippo signaling. Proc Natl Acad Sci U S A 113:E6974-E6983
Misra, Jyoti R; Irvine, Kenneth D (2016) Vamana Couples Fat Signaling to the Hippo Pathway. Dev Cell 39:254-266
Sun, Shuguo; Irvine, Kenneth D (2016) Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network. Trends Cell Biol 26:694-704
Ambegaonkar, Abhijit A; Irvine, Kenneth D (2015) Coordination of planar cell polarity pathways through Spiny-legs. Elife 4:
Irvine, Kenneth D; Harvey, Kieran F (2015) Control of organ growth by patterning and hippo signaling in Drosophila. Cold Spring Harb Perspect Biol 7:
Rauskolb, Cordelia; Sun, Shuguo; Sun, Gongping et al. (2014) Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell 158:143-156

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