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
The main focus of the Kourtidis lab is to fully understand the novel interaction of the adherens junctions (AJs) with the RNA interference (RNAi) machinery, as well as with other RNA-associated complexes.
The AJs is a major cell-cell adhesion structure, playing a fundamental role in the development and maintenance of the normal epithelial phenotype. The core AJs’ receptor in epithelial tissues is E-cadherin (Ecad), which is stabilized and regulated by the proteins called the catenins, such as p120 catenin (p120). Disruption of the AJs has been associated with several pathophysiological abnormalities and diseases, including cancer. In an effort to resolve the role of the AJs in cell behavior, we recently uncovered a novel association of the AJs with the RNAi machinery. In particular, we demonstrated that a p120-binding partner called PLEKHA7 recruits the microprocessor complex and its core components DROSHA and DGCR8 to the apical AJs at the zonula adherens (ZA). The microprocessor is the RNAi complex that mediates the first step in the miRNA biogenesis pathway. Through this mechanism, the AJs regulate the processing and levels of a number of miRNAs, such as miR-30b, in order to suppress the expression of pro-tumorigenic markers, including SNAI1, MYC and CCND1, thus maintaining the normal epithelial phenotype. The discovery of a functional microprocessor outside the nucleus and its regulation by junctional proteins was an unexpected finding, since for a long time it was thought that the microprocessor resides and functions solely in the nucleus. These findings bridged for the first time the fields of cell-cell adhesion and RNAi biology, introducing a new area of investigation.
Our follow-up data obtained by confocal microscopy of fully polarized epithelial monolayers and high-throughput systems biology approaches, such as proteomics, miRNA arrays, RNA-CLIP, qPCR arrays, and next generation sequencing, reveal that the interaction of the AJs with RNA complexes, mRNAs, and miRNAs is extensive. This suggests that there is broad regulation of gene expression by the AJs at the post-transcriptional level. Elucidating all the modes and details of this mechanism and its role in regulating cell behavior is the main goal of our research. We are also investigating the implications of this mechanism in disease, primarily in cancer progression, based on findings showing that: a) loss of this mechanism is widespread in several types of cancer; b) this loss promotes pro-tumorigenic signaling and aberrant cell growth. Since this mechanism is a property of non-transformed cells, numerous questions also emerge regarding its essential function in normal tissues. Several research directions that stem from the above findings are in progress or are about to be initiated in our lab.
Association of the AJs with the RNAi machinery regulates cell growth. (a) Reconstituted confocal x-z image of polarized Caco2 cells stained by immunofluorescence (IF) for PLEKHA7 and p120. PLEKHA7 defines an apical junctional complex at the zonula adherens (ZA). (b) Proteomics revealed the presence of distinct apical (green) and basolateral complexes (red) at the junctions of polarized epithelial cells (common hits are in yellow). A predominant group of proteins associated with the apical complex are RNA-binding proteins (blue) (c) Confocal apical and basal image stacks of polarized Caco2 cells, stained for PLEKHA7 and DROSHA. DAPI is the nuclear stain. PLEKHA7 associates with DROSHA exclusively at the apical ZA. Scale bar: 20 μΜ. (d) In vitro pri-miRNA processing activity assay of IgG (negative control), PLEKHA7, and DGCR8 (positive control) immunoprecipitates (IPs). PLEKHA7 possesses pri-miRNA processing activity. (e) Our current model: the ZA associate with the microprocessor complex via PLEKHA7, to regulate miRNA processing and suppress the expression of mRNAs that promote cell growth.
- 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 Biology2015 17: 1145-1157 [PMID: 26302406].
- 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 Science2013 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.