Cell interactions are crucial to the establishment of order during development, for sensory perception, behavioral responses and homeostasis. Aberrant cellular communication has been largely studied in mammals in situations where it leads to inappropriate cell growth, contributing to neoplasia, or in context of genetically-inherited disease. In invertebrates, such as the fruitfly, Drosophila, it has been possible to use sophisticated genetic and molecular techniques to study mechanisms of cell communication and their developmental roles. One of the major pathways for communication between cells involves the stimulation of the synthesis of cyclic AMP (cAMP) in response to a specific extracellular signal. An intracellular cAMP signal is generally relayed by activation of cAMP-dependent protein kinase (PKA), which phosphorylates specific target proteins to alter their activity. The general objective of our research is to define the biological roles of PKA in Drosophila. We have found the PKA has several important behavioral and developmental roles in Drosophila but this research proposal concentrates on a single developmental function, the participation of PKA in the Hedgehog signal transduction pathway. Hedgehog is a secreted protein that was first discovered in Drosophila but which has close homologs in vertebrates. In Drosophila and in vertebrates Hedgehog proteins function in early development in many different tissues to direct the fates of large groups of cells according to their position. In mammals, aberrant Hedgehog signaling can result in extreme craniofacial defects (cyclopia), limb deformities, defects in ribs, spinal column and motor neuron formation or a propensity for basal cell carcinomas. Remarkably, many features of Hh signaling appear to be conserved between Drosophila and vertebrates, including the participation of PKA.
We aim to determine exactly how PKA acts to allow transduction of a Hh signal by identifying crucial PKA substrates, detailing the effects of PKA and Hh on a transcription factor (called Cubitus interruptus ) that mediate responses to Hedgehog and determining the outcome of simultaneous alteration of the activities of PKA and other putative Hedgehog signal transduction molecules. In this way we aim to understand a highly conserved role of PKA that governs development and cell growth in a multitude of organisms from flies to man.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041815-12
Application #
6180468
Study Section
Genetics Study Section (GEN)
Program Officer
Zatz, Marion M
Project Start
1989-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
12
Fiscal Year
2000
Total Cost
$302,573
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Garcia-Garcia, Elisa; Little, Jamie C; Kalderon, Daniel (2017) The Exon Junction Complex and Srp54 Contribute to Hedgehog Signaling via ci RNA Splicing in Drosophila melanogaster. Genetics 206:2053-2068
Zadorozny, Eva V; Little, Jamie C; Kalderon, Daniel (2015) Contributions of Costal 2-Fused interactions to Hedgehog signaling in Drosophila. Development 142:931-42
Marks, Steven A; Kalderon, Daniel (2011) Regulation of mammalian Gli proteins by Costal 2 and PKA in Drosophila reveals Hedgehog pathway conservation. Development 138:2533-42
Zhou, Qianhe; Kalderon, Daniel (2011) Hedgehog activates fused through phosphorylation to elicit a full spectrum of pathway responses. Dev Cell 20:802-14
Gleason, Julie E; Eisenmann, David M (2010) Wnt signaling controls the stem cell-like asymmetric division of the epithelial seam cells during C. elegans larval development. Dev Biol 348:58-66
Zhou, Qianhe; Kalderon, Daniel (2010) Costal 2 interactions with Cubitus interruptus (Ci) underlying Hedgehog-regulated Ci processing. Dev Biol 348:47-57
Vied, Cynthia; Kalderon, Daniel (2009) Hedgehog-stimulated stem cells depend on non-canonical activity of the Notch co-activator Mastermind. Development 136:2177-86
Smelkinson, Margery G; Zhou, Qianhe; Kalderon, Daniel (2007) Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. Dev Cell 13:481-95
Zhou, Qianhe; Apionishev, Sergey; Kalderon, Daniel (2006) The contributions of protein kinase A and smoothened phosphorylation to hedgehog signal transduction in Drosophila melanogaster. Genetics 173:2049-62
Smelkinson, Margery G; Kalderon, Daniel (2006) Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr Biol 16:110-6

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