We propose to examine the role of G protein coupled receptors (GPCRs) in two related physiological events - secretion and cellular senescence. The secretion of important molecules such as hormones and cytokines are regulated by GPCRs but the mechanistic basis of this regulation is not clear. We have discovered that G protein 23 complexes translocate to the Golgi on GPCR activation and induce secretory vesicle formation in the trans-Golgi. Extracellular signals can thus regulate secretion through 23 translocation.
Our first aim i s to test whether 23 translocation plays a role in GPCR regulation of cathepsin D secretion from a lung carcinoma cell and insulin from a pancreatic beta cell. We have found that secretion of cathepsin D, a protease that promotes tumor growth and metastasis, is regulated by a bradykinin receptor. Insulin secretion is also known to be regulated by GPCRs, including the M3 muscarinic receptor.
The second aim i s to examine the potential role of receptor induced G protein 23 complex translocation in cellular senescence.
The third aim i s to uncover mechanisms at the basis of GPCR regulation of senescence. Cellular senescence is a process by which stressed cells stop dividing but remain viable. It is thought to play contradictory roles - protecting the cell from cancerous growth but promoting proliferation of surrounding pre-neoplastic cells through enhanced secretion of various molecules. We propose to pursue these aims based on recent results that a translocation proficient G protein 3 subunit induces senescence. The role of GPCRs in cellular senescence is not clearly understood although they are the major sensors of extracellular cues. Identifying the molecular mechanisms at the basis of GPCR regulation of secretion and senescence will provide novel targets for the design of therapeutic interventions that can have an impact on cancer, diabetes and the deleterious effects of ageing.

Public Health Relevance

The altered secretion of molecules plays an important role in disease -- cathepsin D in cancer and insulin in diabetes. Cellular senescence is thought to be cancer protective by stopping cell division but the increased secretion of molecules from these cells is thought to encourage tumor formation in surrounding tissue. We propose to identify mechanisms that regulate secretion of these molecules and cellular senescence. Identifying the mechanisms can provide new targets for therapeutic approaches to address cancer, diabetes and the deleterious effects of ageing.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069027-07
Application #
8214550
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2004-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$319,770
Indirect Cost
$109,395
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Meshik, Xenia; O'Neill, Patrick R; Gautam, N (2018) Optogenetic Control of Cell Migration. Methods Mol Biol 1749:313-324
O'Neill, Patrick R; Castillo-Badillo, Jean A; Meshik, Xenia et al. (2018) Membrane Flow Drives an Adhesion-Independent Amoeboid Cell Migration Mode. Dev Cell 46:9-22.e4
O'Neill, Patrick R; Kalyanaraman, Vani; Gautam, N (2016) Subcellular optogenetic activation of Cdc42 controls local and distal signaling to drive immune cell migration. Mol Biol Cell 27:1442-50
Kim, Seungil; Barry, Devin M; Liu, Xian-Yu et al. (2016) Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations. Sci Signal 9:ra71
Karunarathne, W K Ajith; O'Neill, Patrick R; Gautam, Narasimhan (2015) Subcellular optogenetics - controlling signaling and single-cell behavior. J Cell Sci 128:15-25
O'Neill, P R; Gautam, N (2015) Optimizing optogenetic constructs for control over signaling and cell behaviours. Photochem Photobiol Sci 14:1578-85
Giri, Lopamudra; Patel, Anilkumar K; Karunarathne, W K Ajith et al. (2014) A G-protein subunit translocation embedded network motif underlies GPCR regulation of calcium oscillations. Biophys J 107:242-54
O'Neill, Patrick R; Giri, Lopamudra; Karunarathne, W K Ajith et al. (2014) The structure of dynamic GPCR signaling networks. Wiley Interdiscip Rev Syst Biol Med 6:115-23
Zhao, Zhong-Qiu; Liu, Xian-Yu; Jeffry, Joseph et al. (2014) Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 84:821-34
O'Neill, Patrick R; Gautam, N (2014) Subcellular optogenetic inhibition of G proteins generates signaling gradients and cell migration. Mol Biol Cell 25:2305-14

Showing the most recent 10 out of 25 publications