After decades of research efforts and billions of dollars in cost, diabetes and obesity still stand as major health challenges in the developed and developing worlds. The elusive nature of the metabolic disorders stems largely from incomplete understanding of the growth factor signaling pathways that regulate cellular homeostasis in different metabolic cell types. Two long-standing questions include: 1) How do cell membrane bound receptors directly mediate their effects on gene expression in the nucleus thereby regulating a cell's response to a metabolic challenge and 2) Whether insulin receptor (IR) and insulin-like growth factor-1 receptors (IGF1R) that activate common downstream proteins in their signaling pathways, have specific and distinct gene targets that would be suitable for novel drug targets for each receptor. Our work presents the novel evidence that IR and IGF1R, classic cell membrane bound receptors, show ligand-dependent translocation to the nucleus of mouse and human cells. Our genome-wide chromatin immunoprecipitation (ChIP) sequencing analyses provides compelling evidence for the direct recruitment of IR and IGF1R to genomic sites, unfolding a novel paradigm that has the potential to address critical scientific questions imperative to therapeutic innovation, that have remained largely unexplored. We believe our findings have the exciting potential to: a) better understand how signals initiated at the cell membrane are translated into a response to regulate gene expression in the nucleus, b) delineate the differences in IR and IGF1R actions and their response to growth factor stimuli to regulate metabolic function, and c) identify novel players and mechanisms of growth factor signaling that impact both the genetic and epigenetic mechanisms across several metabolic tissues, and hence have broad implications for the treatment of metabolic diseases and cancer.

Public Health Relevance

We propose to continue to focus on investigating the roles of the insulin and IGF-1 receptors in regulating islet biology. Specifically we will examine how the cell membrane receptors shuttle to the nucleus in mammalian cells to impact epigenetic and genetic mechanisms. This approach will likely yield novel insights into the regulation of metabolic cells with the possibility of identifying new therapeutic targets to counter metabolic diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK067536-10
Application #
8830524
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (03))
Program Officer
Sato, Sheryl M
Project Start
2004-03-01
Project End
2018-08-31
Budget Start
2014-09-18
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
$413,854
Indirect Cost
$163,854
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Mezza, Teresa; Shirakawa, Jun; Martinez, Rachael et al. (2016) Nuclear Export of FoxO1 Is Associated with ERK Signaling in β-Cells Lacking Insulin Receptors. J Biol Chem 291:21485-21495
Takatani, Tomozumi; Shirakawa, Jun; Roe, Michael W et al. (2016) IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Sci Rep 6:28177
Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K et al. (2016) Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation. Cell Rep 15:460-70
Ghanem, Simona S; Heinrich, Garrett; Lester, Sumona G et al. (2016) Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem 291:980-8
Dirice, Ercument; Walpita, Deepika; Vetere, Amedeo et al. (2016) Inhibition of DYRK1A Stimulates Human β-Cell Proliferation. Diabetes 65:1660-71
Dirice, Ercument; Kulkarni, Rohit N (2016) Harnessing immune cells to enhance β-cell mass in type 1 diabetes. J Investig Med 64:14-20
Teo, Adrian Kee Keong; Lau, Hwee Hui; Valdez, Ivan Achel et al. (2016) Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia. Stem Cell Reports 6:357-67
Mezza, Teresa; Sorice, Gian P; Conte, Caterina et al. (2016) β-Cell Glucose Sensitivity Is Linked to Insulin/Glucagon Bihormonal Cells in Nondiabetic Humans. J Clin Endocrinol Metab 101:470-5
Shirakawa, J; Kulkarni, R N (2016) Novel factors modulating human β-cell proliferation. Diabetes Obes Metab 18 Suppl 1:71-7
Singhal, Garima; Fisher, Ffolliott Martin; Chee, Melissa J et al. (2016) Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas. PLoS One 11:e0148252

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