Worming to Complete the Insulin/IGF-1 Signaling Cascade: A Dissertation
Authors
Padmanabhan, SrivatsanFaculty Advisor
Heidi A. Tissenbaum Ph.D.Academic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
Molecular, Cell and Cancer BiologyDocument Type
Doctoral DissertationPublication Date
2009-04-17Keywords
Insulin-Like Growth Factor ICaenorhabditis elegans
Caenorhabditis elegans Proteins
Insulin
Proto-Oncogene Proteins c-akt
Signal Transduction
Amino Acids, Peptides, and Proteins
Animal Experimentation and Research
Hormones, Hormone Substitutes, and Hormone Antagonists
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Show full item recordAbstract
The insulin/IGF-1 signaling (IIS) was initially identified in C. elegansto control a developmental phenotype called dauer. Subsequently, it was realized that lifespan was extended by mutations in this pathway and became an intense focus of study. The IIS pathway regulates growth, metabolism and longevity across phylogeny and plays important roles in human disease such as cancer and diabetes. Given the large number of cellular processes that this pathway controls, understanding the regulatory mechanisms that modulate insulin/IGF-1 signaling is of paramount importance. IIS signaling is a very well-studied kinase cascade but few phosphatases in the pathway are known. Identification of these phosphatases, especially those that counteract the activity of the kinases, would provide a better insight into the regulation of this critical pathway. Study of serine/threonine phosphatases is hampered by the lack of appropriate reagents. In Chapter II, we discuss the design and results of an RNAi screen of serine/threonine phosphatases performed in C. elegans using dauer formation as a phenotypic output. We identified several strong regulators of dauer formation and in Chapter III, proceed to characterize one of the top candidates of our screen, pptr-1. We show that pptr-1 regulates the IIS and thereby affects lifespan, development and metabolism in C .elegans. pptr-1gene encodes a protein with high homology to the mammalian B56 family of PP2A regulatory subunits. PP2A is a ubiquitously expressed phosphatase that is involved in multiple cellular processes whose specificity determined by its association with distinct regulatory subunits. Our studies using C. elegans provides mechanistic insight into how the PP2A regulatory subunit PPTR-1 specifically modulates AKT-1 activity by regulating its phosphorylation status in the context of a whole organism. Furthermore, we show that this mechanism of regulation is conserved in mammals.DOI
10.13028/40am-yf26Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31747Rights
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10.13028/40am-yf26