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Molecular interplay of 'STIM1-TRPC1-Caveolin1' orchestrate epithelial cell proliferation.

AIM: To investigate the role of TRPC1-mediated calcium signals in cell proliferation.

INTRODUCTION: Calcium ([Ca.sup.2+]) is a major signaling molecule in both excitable and non-excitable cells, where it modulates a variety of cellular functions ranging from cell growth to differentiation to cell death. One of the prime cellular requirements of [Ca.sup.2+] is during cell-cycle progression. Transit of proliferating cells through the synthesis (S) and mitosis (M) phases of the cell cycle require elevated levels of cytosolic [Ca.sup.2+]. Increase in cytosolic [Ca.sup.2+] then engages a variety of local and global changes including, transcriptional regulation coupled to cell proliferation (1). In order to carry out these physiological functions, cells employ plasma membrane (PM) [Ca.sup.2+]channels to facilitate cytosolic [Ca.sup.2+] entry. Transient receptor canonical-1 (TRPC 1) constitute an integral component of PM [Ca.sup.2+] channels that initiate [Ca.sup.2+] entry following the depletion of endoplasmic reticulum (ER) [Ca.sup.2+] , a process referred to as store-operated [Ca.sup.2+] entry (SOCE) [2]. Recently, Stromal interaction molecule-1 (STIM1) has been identified to regulate SOCE by coupling ER store-depletion to activation of PM [Ca.sup.2+] channels (3). Additionally, we have recently identified that the association of TRPC1 with PM lipid raft/caveolar microdomains and its major structural protein Caveolin1 (Cav1) is a key parameter for the channel activation (4). PM lipid raft/caveolar microdomains represent a major cellular compartment that facilitates several signal transduction events, including [Ca.sup.2+] influx (5). Thus, we hypothesized that both STIM1 and Cav1 will play a significant role in activating TRPC1-mediated [Ca.sup.2+] entry and thereby regulate cell proliferation.

EXPERIMENTS/RESULTS: In this study, we have evaluated the significance of TRPC1-mediated [Ca.sup.2+] influx in transcriptional activation, cell proliferation and migration of epithelial cells. In human submandibular gland (HSG) cells as well as in human epidermal keratinocytes (HaCaT) we demonstrate that over-expression of TRPC1 augmented cell proliferation whereas, silencing of TRPC1 by siRNA (small interfering RNA) or expression of the channels' pore-mutant significantly inhibited proliferation. Under similar expression condition, comparable modulation of NFkB mediated transcriptional regulation was observed. Pharmacological inhibition of TRPC1 channels reduced the migrating potential of HaCaT cells in vitro in response to growth factor stimulation. We have identified a direct association of TRPC1 with caveolar microdomains, Cav1 and STIM1 respectively. Additionally since, TRPC1 is localized to caveolar microdomains and physically associated with" Cav1, we hypothesized that over-expression of Cav1 will amplify TRPC1-mediated [Ca.sup.2+] influx and associated physiological responses. On the contrary, however, increased expression of Cav1 significantly inhibited cell migration and progression of cell-cycle. This inhibitory effect of Cav1 on TRPC 1 function was circumvented by increased expression of STIM1. Following ER [Ca.sup.2+] store depletion, STIM1 displaced Cav1 from TRPC1 resulting in an increased TRPC1-STIM1 and decreased TRPC1-Cav1 association, thereby activating SOCE. Thus, the relative changes in 'TRPC1-STIM1 and 'TRPC1-Cav1' associations are crucial for [Ca.sup.2+] influx mediated proliferative response of epithelial cells.

CONCLUSION: In conclusion, we propose that the association of TRPC1 with Cav1 is required for targeting the channel to specific PM compartments however, following ER store-depletion, the dissociation of the caveolae-associated 'TRPC1-Cav1' complex by STIM1 is imperative for the activation of SOCE and cell proliferation. Thus, this molecular cross-talk between 'STIM1-TRPC1-Cav1' puts forward a novel regulatory paradigm of signal transduction from PM to nucleus. REFERENCES:

(1.) Berridge, M.J., Bootman, M.D., and Roderick, H.L. (2003) Nat. Rev. Mol. Cell. Biol. 4, 517-529.

(2.) Parekh A.B., and Putney, J.W. (2005) Physiol. Rev. 85,757-810.

(3.) Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store- operated Ca2+ channel function (2005). J Cell Biol. May 9; 169(3):435-45.

(4.) Pani B, Ong HL, Liu X, Rauser K, Ambudkar IS, Singh BB. (2008) Lipid rafts determine clustering of STIM1 in endoplasmic reticulum-plasma membrane junctions and regulation of store-operated Ca2+ entry (SOCE). J Biol Chem, 283, 17333-40.

(5.) Simons, K., and Toomre, D. (2000) Nat Rev Mol Cell Biol. 1, 31-39.

Funding: Grant support from the NSF (0548733) and the NIH (DE017102, 5P20RR017699) is acknowledged.

Biswaranjan Pani * and Brij B. Singh

Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201.
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Author:Pani, Biswaranjan; Singh, Brij B.
Publication:Proceedings of the North Dakota Academy of Science
Date:Apr 1, 2010
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