Education:BS Biology, Aristotle University of Thessaloniki, Greece (1998)
PhD Molecular Biology, Aristotle University of Thessaloniki, Greece (2004)
Postdoctoral Fellow, Molecular Biology of Cancer, State University of New York, USA
Senior Research Fellow, Cellular and Molecular Biology of Cancer, Mayo Clinic, USA
Research in our lab focuses on fully understanding: a) a novel interaction of the adherens junctions with the RNA interference (RNAi) machinery and other RNA-associated complexes, and b) the role of this mechanism in regulating cell behavior in normal and diseased tissues.
The adherens junctions are critical cell-cell adhesion structures, playing a fundamental role in the development and maintenance of the normal tissue architecture. E-cadherin is the core adhesion receptor in epithelial tissues and is stabilized through its association with the catenin family of proteins, such as p120 catenin (p120). Disruption of adherens junctions results in loss of tissue integrity and has been associated with numerous diseases, including cancer. It has been also shown that it results in aberrant cell behavior. In an effort to clarify the mechanism through which the adherens junctions influence cell behavior, we recently discovered a novel association with the RNAi machinery. We have shown that PLEKHA7, a new E-cadherin - p120 partner, recruits the microprocessor and RNA-induced silencing (RISC) complexes at the adherens junctions. The microprocessor is an integral component of the RNAi machinery that catalyzes the first step of miRNA biogenesis through its core members DROSHA and DGCR8. Until recently, the microprocessor was thought to localize solely in the cell nucleus, however, our work revealed a functional microprocessor at the junctions of differentiated epithelial cells. PLEKHA7 also recruits the core (Ago2, GW182, PABPC1) and several accessory components of RISC, as well as specific sets of miRNAs and mRNAs. RISC catalyzes the miRNA-mediated silencing of mRNAs. By recruiting the microprocessor and RISC, PLEKHA7 promotes processing and function of a set of miRNAs to suppress expression of several regulators of cellular transformation. Our findings revealed co-localization of RNAi complexes, miRNAs, and mRNAs at the epithelial adherens junctions, suggesting for a new epicenter of RNA regulation and a localized function of the RNAi machinery, which has previously gone unnoticed. Importantly, PLEKHA7 depletion results in compromised epithelial integrity, loss of junctional localization and decreased activity of the microprocessor and RISC, decreased miRNA levels and activity, upregulation of a number of growth-promoting mRNAs, and increased anchorage-independent growth, a hallmark of cellular transformation. Taken together, these results identified a direct link between cell-cell adhesion, epithelial integrity and cell behavior, through RNAi and bridged for the first time the fields of cell-cell adhesion and RNA biology, introducing a new area of investigation.
By employing cutting-edge approaches, such as super-resolution microscopy, proteomics, fluorescent in-situ hybridization, RNA-CLIP, and next generation sequencing, we are now discovering an extensive interaction of the adherens junctions with RNA complexes, mRNAs, miRNAs and non-coding RNAs. Elucidating all the molecular details of this mechanism and its role in regulating cell behavior is the main goal of our research. We are particularly interested in investigating the implications of this mechanism in several diseases, such as in cancer. Numerous questions also emerge regarding the physiological role of this mechanism in normal tissue physiology. Several projects that stem from the above findings are currently in progress or are being initiated in our lab.
The E-cadherin - p120 catenin partner PLEKHA7 recruits the microprocessor (DROSHA-DGCR8), the RISC (Ago2-GW182-PABPC1) and sets or miRNAs and mRNAs at the apical adherens junctions, to regulate cell behavior.
- Kourtidis A*, Necela B, Lin WH, Lu R, Feathers RW, Asmann, YW, Thompson EA, Anastasiadis PZ. Cadherin complexes recruit mRNAs and RISC to regulate epithelial cell signaling. Journal of Cell Biology, 2017, 216(10): 3073-85. [PMID: 28877994] *Co-corresponding author (Faculty of 1000: Two Recommendations - 4 stars, to date).
- Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ. A central role for cadherin signaling in cancer. Experimental Cell Research, 2017, 358(1):78-85. [PMID: 28412244]
- Fiorotto R, Villani A, Kourtidis A, Scirpo R, Amenduni M, Cadamuro M, Spirli C, Anastasiadis PZ, Strazzabosco M. CFTR controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology, 2016, Dec;64(6):2118-2134 [PMID: 27629435]
- Kourtidis A & Anastasiadis PZ. Bringing together cell-to-cell adhesion and miRNA biology in cancer research. Future Oncology, 2016, 12: 1211-1214 [PMID: 26923006].
- Kourtidis A & Anastasiadis PZ. PLEKHA7 defines an apical junctional complex with cytoskeletal associations and miRNA-mediated growth implications. Cell Cycle, 2016, 15: 498-505 [PMID: 26822694].
- Kourtidis A, Ngok SP, Pulimeno P, Feathers RW, Carpio LR, Baker TR, Carr JM, Yan IK, Borges S, Perez EA, Storz P, Copland JA, Patel T, Thompson EA, Citi S & Anastasiadis PZ. Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Nature Cell Biology, 2015, 17: 1145-1157 [PMID: 26302406]. (Top read: in the top 1% of the 232,739 tracked articles of a similar age in all journals; Faculty of 1000: Two Recommendations - 4 stars, to date; Nature Medicine: News in Brief, October 2015, 21, 1112–13; Highlighted in BBC news and other news outlets)
- Kourtidis A, Yanagisawa M, Huveldt D, Copland JA & Anastasiadis PZ. Pro-Tumorigenic Phosphorylation of p120 Catenin in Renal and Breast Cancer. PLoS One, 2015, 10: e0129964 [PMID: 26067913].
- Xu D, Chatakonda VK, Kourtidis A, Conklin DS & Shi H. In search of novel drug target sites on estrogen receptors using RNA aptamers. Nucleic Acid Therapeutics, 2014, 24: 226-238 [PMID: 24588102].
- Dachsel JC, Ngok SP, Lewis-Tuffin LJ, Kourtidis A, Geyer R, Johnston L, Feathers R & Anastasiadis PZ. The Rho guanine nucleotide exchange factor Syx regulates the balance of dia and ROCK activities to promote polarized-cancer-cell migration. Molecular and Cellular Biology, 2013, 33: 4909-4918 [PMID: 24126053].
- Eifert C, Wang X, Kokabee L, Kourtidis A, Jain R, Gerdes MJ & Conklin DS. A novel isoform of the B cell tyrosine kinase BTK protects breast cancer cells from apoptosis. Genes Chromosomes and Cancer, 2013, 52: 961-975 [PMID: 23913792].
- Kourtidis A, Ngok SP & Anastasiadis PZ. p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Progress in Molecular Biology and Translational Science,2013, 116: 409-432 [PMID: 23481205].
- Ngok SP, Geyer R, Kourtidis A, Mitin N, Feathers R, Der C & Anastasiadis PZ. TEM4 is a junctional Rho GEF required for cell-cell adhesion, monolayer integrity and barrier function. Journal of Cell Science, 2013, 126: 3271-3277 [PMID: 23729734].
- Ngok SP, Geyer R, Kourtidis A, Storz P & Anastasiadis PZ. Phosphorylation-mediated 14-3-3 protein binding regulates the function of the rho-specific guanine nucleotide exchange factor (RhoGEF) Syx. Journal of Biological Chemistry, 2013, 288: 6640-6650 [PMID: 23335514].
- Ngok SP, Geyer R, Liu M, Kourtidis A, Agrawal S, Wu C, Seerapu HR, Lewis-Tuffin LJ, Moodie KL, Huveldt D, Marx R, Baraban JM, Storz P, Horowitz A & Anastasiadis PZ. VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx. Journal of Cell Biology, 2012, 199: 1103-1115 [PMID: 23253477].
- Kourtidis A, Jain R, Carkner RD, Eifert C, Brosnan MJ & Conklin DS. An RNA interference screen identifies metabolic regulators NR1D1 and PBP as novel survival factors for breast cancer cells with the ERBB2 signature. Cancer Research, 2010, 70: 1783-1792 [PMID: 20160030].
- Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, Kourtidis A, Conklin DS & Aguirre-Ghiso JA. Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Research, 2009, 69: 5664-5672 [PMID: 19584293].
- Kourtidis A, Srinivasaiah R, Carkner RD, Brosnan MJ & Conklin DS. Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity. Breast Cancer Research, 2009, 11: R16 [PMID: 19298655].
- Pantzartzi CN, Kourtidis A, Drosopoulou E, Yiangou M & Scouras ZG. Isolation and characterization of two cytoplasmic hsp90s from Mytilus galloprovincialis (Mollusca: Bivalvia) that contain a complex promoter with a p53 binding site. Gene, 2009, 431: 47-54 [PMID: 19061940].
- Lastro M, Kourtidis A, Farley K & Conklin DS. xCT expression reduces the early cell cycle requirement for calcium signaling. Cellular Signaling, 2008, 20: 390-399 [PMID: 18054200].
- O'Connell CB, Loncarek J, Hergert P, Kourtidis A, Conklin DS & Khodjakov A. The spindle assembly checkpoint is satisfied in the absence of interkinetochore tension during mitosis with unreplicated genomes. Journal of Cell Biology, 2008, 183: 29-36 [PMID: 18824563].
- Ranganathan AC, Ojha S, Kourtidis A, Conklin DS & Aguirre-Ghiso JA. Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Research, 2008, 68: 3260-3268 [PMID: 18451152].
- Evans SC, Kourtidis A, Markham TS, Miller J, Conklin DS & Torres AS. MicroRNA target detection and analysis for genes related to breast cancer using MDLcompress. EURASIP Journal on Bioinformatics and Systems Biology, 2007, 43670 [PMID: 18317504].
- Kourtidis A, Eifert C & Conklin DS. RNAi applications in target validation. Ernst Schering Research Foundation Workshop, 2007, 1-21 [PMID: 17249494].
- Kourtidis A, Drosopoulou E, Nikolaidis N, Hatzi VI, Chintiroglou CC & Scouras ZG. Identification of several cytoplasmic HSP70 genes from the Mediterranean mussel (Mytilus galloprovincialis) and their long-term evolution in Mollusca and Metazoa. Journal of Molecular Evolution, 2006, 62: 446-459 [PMID: 16547643].
- Kourtidis A, Drosopoulou E, Pantzartzi CN, Chintiroglou CC & Scouras ZG. Three new satellite sequences and a mobile element found inside HSP70 introns of the Mediterranean mussel (Mytilus galloprovincialis). Genome, 2006, 49: 1451-1458 [PMID: 17426760].
- Kourtidis A & Scouras ZG. Analysis and characterization of the transcriptional unit of a new Mytilus galloprovincialis (Mollusca: Bivalvia) hsp70 gene. DNA Sequence, 2005, 16: 36-43 [PMID: 16040345].
Full list available here.