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.
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.
|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|
|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|
|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; 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|
|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|
|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|
|Karunarathne, W K Ajith; Giri, Lopamudra; Kalyanaraman, Vani et al. (2013) Optically triggering spatiotemporally confined GPCR activity in a cell and programming neurite initiation and extension. Proc Natl Acad Sci U S A 110:E1565-74|
|Karunarathne, W K Ajith; Giri, Lopamudra; Patel, Anilkumar K et al. (2013) Optical control demonstrates switch-like PIP3 dynamics underlying the initiation of immune cell migration. Proc Natl Acad Sci U S A 110:E1575-83|
|Ajith Karunarathne, W K; O'Neill, Patrick R; Martinez-Espinosa, Pedro L et al. (2012) All G protein Î²Î³ complexes are capable of translocation on receptor activation. Biochem Biophys Res Commun 421:605-11|
Showing the most recent 10 out of 22 publications