Calcium signaling regulates a plethora of cellular functions and thereby plays a critical role in maintaining tissue homeostasis and health. Perturbation in calcium dynamics causes impairment of cellular physiology eventually leading to diseases. The focus of our group is to understand the role of calcium signaling in skin pigmentation, pancreatic tumorigenesis and cancer metastasis. We are aiming to: 1) Delineate the role of calcium dynamics in these pathophysiological conditions; 2) Elucidate detailed molecular mechanisms connecting dysregulated calcium signaling to cancer metastasis and pigmentary disorders; 3) Eventually, we aim to utilize this knowledge to devise strategies for better therapeutic intervention and clinical management of these pathophysiological conditions.

Our laboratory employs multidisciplinary approaches for understanding the role of calcium signaling in cancer metastasis and skin pigmentation. We extensively utilize cell and molecular biology tools, high-end microscopy, electrophysiology, genomics approaches, bioinformatics, in vivo animal models and human patient samples for addressing the research problems. The details of ongoing projects in the laboratory are as follows:

Skin pigmentation

Skin pigmentation plays a vital role in protection against harmful ultra violet (UV) rays. Indeed, tanning is a protective response of the melanocytes for guarding skin from UV induced cancers. Perturbations in pigmentation pathways result in pigmentary disorders like solar lentigo, melasma, and vitiligo. These disorders are considered as social stigma; impart long-term psychological trauma and are huge economic burden on the health care system. The current therapeutic regimes are not efficient in alleviating pigmentation defects. Therefore, it is critical to identify the novel molecular players that regulate pigmentation and devise strategies to target them for calibrating pigmentation. For identifying novel regulators of pigmentation, we performed microarrays on hyperpigmented and hypopigmented primary human melanocytes. Interestingly, we observed significant deviations in the calcium homeostasis in these differentially pigmented cells. However, the significance of calcium dynamics and functional relevance of calcium handling proteins in pigmentation biology remains poorly appreciated. Therefore, we aim to delineate the Calciomics (studies of calcium handling proteins, their interactome and downstream effector proteins) of pigmentation. This program employs live cell imaging, electrophysiology, cell and molecular biology tools and genomics approaches for prioritization of the leads and in vivo validation is performed in zebrafish and mice models. After recognizing the key players modulating pigmentation, we aim to develop strategies for targeting them therapeutically to calibrate skin pigmentation.

Relevant publications:

1. Tanwar J, Ahuja K, Sharma A, Sehgal P, Ranjan G, Sultan F, Priya A, Venkatesan M, Yenamandra VK, Singh A, Madesh M, Sivasubbu S and Motiani RK# (2023). Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis. bioRxiv 2023 May 26: 2023.05.26.542250 https://doi.org/10.1101/2023.05.26.542250
2. Sharma N, Sharma A and Motiani RK# (2023). A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator. Cell Calcium 2023 May; 111:102705. https://doi.org/10.1016/j.ceca.2023.102705
3. Tanwar J, Sharma A, Saurav S, Shyamveer, Jatana N and Motiani RK^# (2022). MITF is a novel transcriptional regulator of the calcium sensor STIM1: significance in physiological melanogenesis. Journal of Biological Chemistry 2022 Nov 7:102681.
4. Sultan F, Basu R, Murthy D, Kochar M, Attri KS, Aggarwal A, Kumari P, Dnyane P, Tanwar J, Motiani RK, Singh A, Gadgil C, Bhavesh NS, Singh PK, Natarajan VT, Gokhale RS (2022). Temporal analysis of melanogenesis identifies fatty acid metabolism as key skin pigment regulator. PLoS Biology 2022 May 18;20(5):e3001634.
5. Tanwar J, Saurav S, Basu R, Singh JB, Priya A, Dutta M, Santhanam U, Joshi M, Madison S, Singh A, Nair N, Gokhale RS and Motiani RK^# (2022). Mitofusin-2 negatively regulates melanogenesis by modulating Mitochondrial ROS generation. Cells 2022 Feb 16;11(4):701.
6. Motiani RK^#, Tanwar J, Raja DA, Vashisht A, Khanna S, Sharma S, Srivastava S, Sivasubbu S, Natarajan VT and Gokhale RS^# (2018). STIM1 activation of adenylyl cyclase 6 connects Ca2+ and cAMP signaling during melanogenesis. EMBO Journal. 2018 Mar 1;37(5)
^#Corresponding Author

Pancreatic Cancer

Pancreatic Cancer (PC) is one of the deadliest cancers with mean survival time of less than 5 years. Majority of the PC deaths are associated with secondary metastasis. For developing effective treatment strategies, it is necessary to understand the molecular mechanisms that drive PC progression and metastasis. Calcium signaling plays a critical role in tumorigenesis by regulating the hallmarks of cancer progression such as cellular proliferation, invasion and metastasis. However, precise spatio-temporal contribution of calcium handling machinery in pancreatic cancer progression and metastasis remains largely unappreciated. Therefore, our aim is to determine the role of calcium dynamics and associated channels/transporters in pancreatic cancer biology. We are utilizing cell and molecular biology tools, high-speed live cell and super-resolution microscopy along with animal models such as zebrafish and mice for addressing this research question. The overarching goal of this program is to identify key oncogenic targets and devise strategies for therapeutically managing them to abrogate pancreatic tumorigenesis and/or metastasis.

Relevant publications:

1. Arora S, Tanwar J, Sharma N, Saurav S and Motiani RK^# (2021). Orai3 regulates pancreatic cancer metastasis by encoding a functional store operated calcium entry channel. Cancers 2021 Nov 25;13(23):5937.
2. Tanwar J, Arora S and Motiani RK^# (2020) Orai3: Oncochannel with therapeutic potential. Cell Calcium 2020 Sep; 90:102247.
3. Vashisht A, Tanwar J and Motiani RK^#(2018). Regulation of proto-oncogene Orai3 by miR18a/b and miR34a. Cell Calcium 2018 Nov; 75:101-111.
4. Vashisht A, Trebak M and Motiani RK^# (2015). STIM and Orai Proteins as novel targets for Cancer therapy. Am J Physiol: Cell Physiol. 2015 Oct 1;309(7):C457-69.
^#Corresponding Author

• Wellcome Trust/DBT India Alliance Intermediate Fellow, 2020.
• DST-International Travel Award for attending and serving as Discussion Leader at Gordon Research Seminar (Calcium Signaling) Italy, 2017
• INSPIRE Faculty Award 2013
• International Travel Award for oral presentation at Gordon Research Seminar (Calcium Signaling) Pisa, Italy 2013
• Young Investigator Award, Regional Center for Biotechnology 2012
• Best Graduate Student Alumni Award, Albany Medical College, USA, 2012
• National Travel Award for oral presentation at Gordon Research Seminar (Calcium Signaling) Maine, USA, 2011
• Richard H. Edmonds Leadership Award, Albany Medical College, USA, 2010
• Annual Alumni Research Award, Albany Medical College, USA, 2009
• Pre-Doctoral Fellowship, Albany Medical College, USA, 2007-2012
• All India Rank 2294 in All India Pre Medical Test, 2002
• All India Rank 170 in All India Pre Veterinary Test, 2002

1. Chatterjee O, Jana J, Panda S, Dutta A, Sharma A, Saurav S, Motiani RK, Weisz K, Chatterjee S (2024).Remodeling Ca2+ dynamics by targeting a promising E-box containing G-quadruplex at ORAI1 promoter in triple-negative breast cancer. bioRxiv 2024 March 28: 2024.03.28.587164.
2. Prajapat SK, Mishra L, Khera S, Owusu SD, Ahuja K, Sharma P, Choudhary E, Chhabra S, Kumar N, Singh R, Kaushal PS, Mahajan D, Banerjee A, Motiani RK, Vrati S, and Kalia M (2024). Methotrimeprazine is a neuroprotective antiviral in Japanese encephalitis virus infection via adaptive ER stress and autophagy. EMBO Molecular Medicine 2024 Jan 2.
3. Sengupta A, Vinayagamurthy S, Soni D, Deb R, Mukherjee AK, Dutta S, Jaiswal J, Yadav M, Sharma S, Bagri S, Roy SS, Singh A, Khanna D, Bhatt AK, Sharma A, Saurav S, Motiani RK and Chowdhury S (2023). Telomeres control regulation of the human Telomerase (hTERT) gene through non-telomeric TRF2 and independent of Telomere looping. bioRxiv 2023 Oct 9: 2023.10.09.561466.
4. Tanwar J, Ahuja K, Sharma A, Sehgal P, Ranjan G, Sultan F, Priya A, Venkatesan M, Yenamandra VK, Singh A, Madesh M, Sivasubbu S and Motiani RK^# (2023). Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis.bioRxiv 2023 May 26: 2023.05.26.542250
5. Sharma N, Sharma A and Motiani RK^# (2023). A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator.Cell Calcium 2023 May; 111:102705
6. Tanwar J, Sharma A, Saurav S, Shyamveer, Jatana N and Motiani RK^# (2022). MITF is a novel transcriptional regulator of the calcium sensor STIM1: significance in physiological melanogenesis.Journal of Biological Chemistry 2022 Nov 7;298(12):102681.
7. Sultan F, Ahuja K, Motiani RK^# (2022). Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis. Cell Calcium 2022 Sep; 106:102637.
8. Tanwar J, Saurav S, Basu R, Singh JB, Priya A, Dutta M, Santhanam U, Joshi M, Madison S, Singh A, Nair N, Gokhale RS and Motiani RK^# (2022). Mitofusin-2 negatively regulates melanogenesis by modulating Mitochondrial ROS generation. Cells 2022 Feb 16;11(4):701
9. Sultan F, Basu R, Murthy D, Kochar M, Attri KS, Aggarwal A, Kumari P, Dnyane P, Tanwar J, Motiani RK, Singh A, Gadgil C, Bhavesh NS, Singh PK, Natarajan VT, Gokhale RS (2022). Temporal analysis of melanogenesis identifies fatty acid metabolism as key skin pigment regulator. PLoS Biology 2022 May 18;20(5):e3001634
10. Arora S, Tanwar J, Sharma N, Saurav S and Motiani RK^# (2021). Orai3 regulates pancreatic cancer metastasis by encoding a functional store operated calcium entry channel. Cancers, 23:5937
11. Saurav S, Tanwar J, Ahuja K and Motiani RK^# (2021) Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance. Mol Aspects Med, 81:101004
12. Tanwar J, Singh JB, Motiani RK^# (2021). Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics. Mitochondrion. 2021 Mar, 57: 9-22.
13. Sehgal P, Mathew S, Sivadas A, Ray A, Tanwar J, Vishwakarma S, Rajan G, Shamsudheen KV, Bhoyar RC, Pateria A, Leonard E, Lalwani M, Vats A, Pappuru RR, Tyagi M, Jakati S, Sengupta S, Binukumar BK, Chakrabarti S, Kaur I, Motiani RK, Scaria V and Sivasubbu S (2021). LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy. EMBO J (2021) e107134.
14. Sharma N, Arora S, Saurav S, Motiani RK^# (2020) Pathophysiological Significance of Calcium Signaling at Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs). Current Opinion in Physiology, 17:234
15. Raja D A, Subramaniam Y, Aggarwal A, Gotherwal V, Babu A, Tanwar J, Motiani R K, Sivasubbu S, Gokhale R S, Natarajan V T (2020) Histone variant dictates fate biasing of neural crest cells to melanocyte lineage. Development 2020 Mar 12;147(5):dev182576. doi: 10.1242/dev.182576.
16. Tanwar J, Arora S, Motiani RK^# (2020) Orai3: Oncochannel with therapeutic potential. Cell Calcium 2020 doi.org/10.1016/j.ceca.2020.102247.
17. Grover R, Burse SA, Shankrit S, Aggarwal A, Kirti K, Narta K, Srivastav R, Ray AK, Malik G, Vats A, Motiani RK, Thukral L, Roy SS, Bhattacharya S, Sharma R, Natarajan K, Mukerji M, Pandey R, Gokhale RS and Natarajan VT (2019). Myg1 exonuclease couples the nuclear and mitochondrial translational programs through RNA processing. Nucleic Acid Research. 2019 June 47(11):5852-5866.
18. Selokar NL, Sharma P, Saini M, Sheoran S, Rajendran R, Kumar D, Sharma RK, Motiani RK, Kumar P, Jerome A, Khanna S, Yadav PS (2019). Success cloning of a superior breeding bull. Sci Rep. 2019 Aug 6;9(1):11366.
19. Motiani RK^#, Tanwar J, Raja DA, Vashisht A, Khanna S, Sharma S, Srivastava S, Sivasubbu S, Natarajan VT and Gokhale RS# (2018). STIM1 activation of adenylyl cyclase 6 connects Ca2+ and cAMP signaling during melanogenesis. EMBO Journal. 2018 Mar 1;37(5)
20. Tanwar J and Motiani RK^# (2018). Role of SOCE architects STIM and Orai proteins in Cell Death. Cell Calcium 2018 Jan; 69:19-27.
21. Vashisht A, Tanwar J and Motiani RK^# (2018). Regulation of proto-oncogene Orai3 by miR18a/b and miR34a. Cell Calcium 2018 Nov; 75:101-111.
22. Nissim TB, Zhang X, Elazar A, Roy S, Stolwijk JA, Zhou Y, Motiani RK, Gueguinou M, Hempel N, Gill DL, Trebak M and Sekler I (2017). Mitochondria control store-operated Ca2+ entry through Na+ and redox signals. EMBO Journal. 2017 Mar 15; 36(6):797-815
23. Tanwar J, Trebak M and Motiani RK^# (2017). Role of STIM and Orai proteins in Vascular Disorders. Adv Exp Med Biol. 2017; 993:425-452.
24. Kundu S, Bansal S, Muthukumarasamy KM, Sachidanandan C, Motiani RK^# and Bajaj A^# (2017). Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems. Med Chem Comm. 2017 8 (12), 2248-2257.
25. Singh VP*, Motiani RK*, Singh A, Malik G, Aggarwal R, Singh KP, Wani MR, Gokhale SB, Natarajan VT, Gokhale RS (2016). Water Buffalo (Bubalus bubalis) as a spontaneous animal model of Vitiligo. Pigment Cell Melanoma Res. 2016 Jul;29(4):465-9.
26. Singh M, Bansal S, Kundu S, Bhargava P, Singh A, Motiani RK, Shyam R, Vedagopuram S, Sengupta S and Bajaj A (2015). Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy. Med Chem Comm. 2015, Jan: 6(1);192-201.
27. Vashisht A, Trebak M and Motiani RK^# (2015). STIM and Orai Proteins as novel targets for Cancer therapy. Am J Physiol: Cell Physiol. 2015 Oct 1;309(7):C457-69.
28. Singh M, Kundu S, Amarendar Reddy M, Vedagopuram S, Motiani RK, Sengupta S, Srivastava A and Bajaj A (2014). Injectable small molecule hydrogel as a potential nanocarrier for localized and sustained in vivo delivery of doxorubicin. Nanoscale, 2014 Oct 9;6(21):12849-55.
29. Motiani RK, Zhang X, Harmon KE, Keller RS, Matrougui K, Bennett JA & Mohamed Trebak (2013). Orai3 is an Estrogen Receptor α-Regulated Ca2+ Channel that Promotes Tumorigenesis. FASEB Journal. 2013 Jan; 27(1): 63-75.
30. Motiani RK, Hyzinski-García MC, Zhang X, Henkel M, Mongin AA and Trebak M (2013). STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastomas invasion. Pflugers Arch-European Journal of Physiology. 2013 Sep; 465(9):1249-60.
31. González-Cobos JC, Zhang X, Zhang W, Ruhle B, Motiani RK, Schindl R, Muik M, Bisaillon JM, Shinde AV, Fahrner M, Singer HA, Matrougui K, Barroso M, Romanin C and Trebak M. (2013). Store-Independent Orai1/3 channels Activated by Intracrine LeukotrineC4 in Neointimal Hyperplasia. Circ. Res. 2013 March 29; 112(7):1013-25.
32. Motiani RK, Stolwijk J, Newton RL, Zhang X and Trebak M (2013). Emerging roles of Orai3 in Patho-Physiology. Channels (Austin). Vol. 7(5): 392-401.
33. Shinde AV, Motiani RK, Zhang X, Abdullaev IF, Adam AP, Gonzalez-Cobos JC, Matrougui K, Vincent PA and Trebak M. (2013). STIM1 controls endothelial barrier function independently of Orai1 and Ca2+ entry. Science Signaling. 2013 Mar 19;6(267):ra18
34. Merlet E, Atassi F, Motiani RK, Mougenot N, Jacquet A, Nadaud S, Capiod T, Trebak M, Lompré AM and Marchand A (2013). miR-424/322 regulates vascular smooth muscle cell phenotype and neointimal formation in rat. Cardiovascular Research. 2013 Jun 1;98(3):458-68.
35. Trebak M, Zhang W, Ruhle B, Henkel MM, González-Cobos JC, Motiani RK, Stolwijk J, Newton RL and Zhang X. (2013). What role for Store Operated Ca2+ Entry in muscle? Microcirculation. 2013 May;20(4):330-6.
36. Zhang X, Gonzalez-Cobos JC, Schindl R, Muik M, Ruhle B, Motiani RK, Bisaillon JM, Zhang W, Fahrner M, Borroso M, Matrougui K, Romanin C and Trebak M (2013). Mechanisms of STIM1 Activation of Store-Independent Leukotriene C4-Regulated Ca2+ Channels. Mol Cell Biol. 2013 Sep; 33(18):3715-23.
37. Vedagopuram S, Bansal S, Motiani RK, Kundu S, Muppu SK, Majumdar TD, Panjamurthy K, Sengupta S and Bajaj A (2013). Design, synthesis, and mechanistic investigations of Bile Acid-Tamoxifen conjugates for breast cancer therapy. Bioconjug Chem. 2013 Sep 18; 24(9):1468-84.
38. Spinelli A*, González-Cobos JC*, Zhang X*, Motiani RK*, Rowan S, Garrett J, Zhang W, Matrougui K, Vincent PA, Singer HA and Trebak M. (2012). STIM1 and Orai1 mediate PDGF-induced airway smooth muscle migration. Pflugers Arch-European Journal of Physiology. November 2012; 464(5): 481-92
39. Motiani RK and Trebak M (2012). STIM1/Orai1-Mediated Store-Operated Calcium Entry in Cardiovascular Disease. Chapter 20 p301-325: Cardiovascular system; Store-operated Ca2+ Entry (SOCE) Pathways: Emerging Signaling Concepts in Human (PATHO) Physiology Springer Publishing Group. ISBN: 978-3-7091-0961-8.
40. González-Cobos JC, Zhang X, Motiani RK, Harmon KE and Trebak M (2012). TRPs to Cardiovascular Disease. Chapter 1.1: TRPs and Cardiovascular Diseases; TRP Channels in Drug Discovery: Methods in Pharmacology and Toxicology. Springer/Humana Press. ISBN 978-1-62703-094-6. DOI: 10.1007/978-1-62703-095-3_1.
41. Zhang W, Halligan KE, Zhang X, Bisaillon JM, Gonzalez-Cobos JC, Motiani RK, Hu G, Vincent PA, Zhou J, Barroso M, Singer HA, Matrougui K and Trebak M (2011).Orai1-mediated ICRAC is essential for Neointima formation after Vascular Injury. Circ. Res. 2011 Aug 19;109(5):534-42 .
42. Motiani RK, Abdullaev IF and Trebak M (2010). A novel native store-operated calcium channel encoded by Orai3: Selective requirement of Orai3 versus Orai1 in Estrogen receptor positive versus Estrogen receptor negative breast cancer cells. J. Biol. Chem. 2010 June 18; 285(25): 19173-83.
43. Bisaillon JM*, Motiani RK*, Gonzalez-Cobos JC*, Potier M, Halligan KE, Alzawahra WF, Barroso M, Singer HA, Jourd'heuil D, Trebak M. (2010). Essential Role for STIM1/Orai1-Mediated Calcium Influx in PDGF-Induced Smooth Muscle Migration. Am J Physiol, Cell Physiol. 2010 May;298(5):C993-1005
44. Potier M*, González JC*, Motiani RK*, Abdullaev IF, Bisaillon JM, Singer HA and Trebak M (2009). Evidence for STIM1- and Orai1-Dependent Store-Operated Ca2+ Influx Through ICRAC in Primary Vascular Smooth Muscle Cells. FASEB Journal. 2009 Aug;23(8):2425-37.
45. Zayed N, Afif H, Chabane N, Mfuna-Endam L, Benderdour M, Martel-Pelletier J, Pelletier JP, Motiani RK, Trebak M, Duval N, Fahmi H (2008). Inhibition of interleukin-1beta-induced matrix metalloproteinases 1 and 13 production in human osteoarthritic chondrocytes by prostaglandin D2. Arthritis Rheum. 2008 Nov;58(11):3530-40.
46. Abdullaev IF, Bisaillon JM, Potier M, González JC, Motiani RK and Trebak M (2008). Stim1 and Orai1 Mediate CRAC Currents and Store-Operated Calcium Entry important for Endothelial Cell Proliferation. Circ Res. 2008 Nov 21; 103(11):1289-99.

(* Co-First Author; # Corresponding Author)