Professor, Biochemistry and Molecular Biology
Phone: 402-559-3826 (Office)
Ph.D., Kobe University, Kobe, Japan, 1983
Student research opportunities in my lab:
Medical students, summer research
Undergraduate students, summer research
Gap junctions, formed of proteins called connexins, are ensembles of several cell-cell channels that signal by permitting the direct exchange of small molecules between the cytoplasmic interiors of contiguous cells (Figure 1). Evidence is mounting that connexins act as tumor suppressors. The assembly of connexins into gap junctions, often called gap junction plaques, is a multi-step process (Figure 1).
Connexins are trans-membrane proteins that span the membrane four times (Figure 2).
Due to the short half-life of connexins (2-5 h), the plaque is in a dynamic state, and is thought to model and remodel constantly through recruitment of newly synthesized connexons to the periphery and through endocytosis of moribund plaque components from the center (Figure 3) or through the endocytosis of the plaque in its entirety. Multiple regulatory mechanisms are utilized in a physiological state and cell-context dependent manner to control gap junction assembly at the site of cell-cell contact. The spatio-temporal events and the cellular factors required for the de novo formation of a nascent gap junction plaque, its growth, and disassembly are poorly understood.
Our ongoing studies explore the role of connexins in the pathogenesis of prostate and pancreatic cancers. We have found that the trafficking and assembly of connexins into gap junctions are impaired in several forms of cancers. This has led us to ask the question: What are the intrinsic and extrinsic determinants that dictate the trafficking and assembly of connexins into gap junctions and what is their relevant contribution? The first project is aimed at elucidating the molecular mechanisms by which cell-cell adhesion molecules, such as cadherins, regulate the formation of gap junctions. Cadherins have been thought to facilitate the assembly of gap junctions by enhancing cell-cell contact; however, the molecular mechanisms involved in this process have remained unexplored. The ongoing research is dissecting the molecular mechanisms by which cell-cell contact dictates the assembly of connexins into gap junctions.
Our second project is aimed at exploring the role of gap junctions in maintaining the polarized and differentiated state of epithelial cells . The importance of investigating this is underscored by the fact that the progression of a variety of carcinomas is characterized by loss of polarized and differentiated state of epithelial cells and epithelial to mesenchymal transformation (EMT). Recent studies have shown that forced expression of connexins ameliorates the EMT-like characteristics acquired by the tumor cells. Also, the maintenance of tight junctions, which are required to maintain the polarized state of epithelial cells , is dependent on the formation of gap junctions. We are exploring the molecular mechanisms by which cell polarization facilitates gap junction assembly and how acquisition of EMT-like characteristics disrupts assembly. Our third project explores the molecular mechanisms by which connexins and gap junctions are endocytosed. We are examining which motifs in connexins regulate the endocytosis of connexins and gap junctions in pancreatic and prostate cancer cell lines. We employ cell and molecular biological and knock- down and knock-in approaches to examine gap junction assembly and disassembly using wild-type and mutant connexins, which are tagged with fluorescent proteins.
Mitra, S., Annamalai, L., Chakraborty, S., Johnson, K., Song, X-H., Batra, S.K., and Mehta, P.P. (2006). Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. Mol. Biol. Cell. 17:5400-5416. Abstract
Andrianafahanana, M., Singh, A.P., Nemos, C., Ponnusamy, M.P., Moniaux, N., Mehta, P.P., Varshney, G.C., Batra, S.K. (2007) IFN-gamma-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: A novel mechanism for IFN-gamma response. Oncogene 26:7251-7261. Abstract
Mehta, P.P. (2007) Introduction: A tribute to cell-to-cell channels. J. Membr. Biol. 217:5-12. Abstract
Mimeault, M., Hauke, R., Mehta, P.P., Batra, S.K. (2007) Recent advances in cancer stem/progenitor cell research: Therapeutic implications for overcoming resistance to the most aggressive cancers. J. Cell Mol. Med. 11:981-1011. Abstract
Mimeault, M., Mehta, P.P., Hauke, R., Henichart, J.P., Depreux, P. Lin, M.F., Batra, S.K. (2007) Improvement of cytotoxic effects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades. Growth Factors 25:400-416. Abstract
Chaturvedi, P., Singh, A.P., Chakraborty, S., Chauhan, S.C., Bafna, S., Meza, J.C., Singh, P.K., Hollingsworth, M.A., Mehta, P.P., Batra, S.K. (2008) MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Res. 68:2065-2070. Abstract
Mimeault, M., Mehta, P.P., Hauke, R., Batra, S.K. (2008) Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies. Endocr. Rev. 29:234-252. Abstract
Chakraborty S, Mitra S, Falk M, Caplan S, Wheelock MJ, Johnson K, Mehta PP. (2010) E-cadherin differentially regulates the assembly of connexin43 and connexin32 into gap junctions in human squamous carcinoma cells. J Biol Chem. 285:10761-10776.
Govindarajan R, Chakraborty S, Johnson KE, Falk MM, Wheelock MJ, Johnson KR, and Mehta PP. (2010) Assembly of connexin43 is differentially regulated by E-cadherin and N-cadherin in rat liver epithelial cells. Mol Biol Cell. 21:4089-4107.
Kelsey L, Katoch P, Johnson KE, Batra SK, and Mehta PP. (2012) Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. PLoS ONE. 7:e32846.
Johnson KE, Mitra S, Katoch P, Kelsey LS, Johnson KR, and Mehta PP. (2013) Phosphorylation on serines 279 and 282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells. Mol Biol Cell. 24:715-33.
Kelsey, L.S., Katoch, P., Ray, A., Lin, M.-F., and Mehta, P: Vitamin D3 regulates the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. PLoS ONE 9, e106437. 2014. PMID 25288420.
Katoch,P., Mitra,S., Ray,A., Kelsey,L.S., Roberts,B., Wahl III JK, Johnson KR, and Mehta,P.P. (2015). The Carboxyl Tail of Connexin32 Regulates Gap Junction Assembly in Human Prostate and Pancreatic Cancer Cells. J Biol Chem 290, 4647-4662. PMID:25548281
Current Grants and Contracts:
Connexins and chemoprevention of prostate cancer progression
4/1/2005 - 2/28/2013
Department of Defense Prostate Cancer Program
Connexins in prostate cancer initiation and progression of prostate cancer
9/1/2009 - 8/31/2012
Nebraska Center for Cellular Signaling
7/1/2008 - 6/30/2013
State of NE (LB506)
Connexin and chemoprevention of prostate cancer
7/1/2012 - 6/30/2013
Department of Defense Prostate Cancer Program
Connexin and cadherin crosstalk in prostate cancer
7/1/2012 - 6/30/2015