Education:
PhD, Department of Pharmacology, Rutgers University, New Jersey Medical School
BS, School of Pharmacy, Aristotle University, Greece
Clinical / Research Interests:
Defining the molecular and cellular function of PKD1/PKD2
The Polycystin 1 (PKD1) and Polycystin 1-like (PKD1-L1, PKD1-L2, and PKD1-L3) proteins constitute a group of cell surface molecules that uniquely combine structural features of both ion channels and G protein–coupled receptors (GPCRs). These proteins frequently assemble into complexes with partially homologous members of the TRP superfamily of ion channels, including PKD2, PKD2-L1, PKD2-L2, and PKD2-L3. Collectively, these complexes mediate a wide range of biological functions, from the establishment of left–right patterning during embryonic development and the regulation of taste sensation to their central involvement in the pathogenesis of Polycystic Kidney Disease. A unifying feature among these proteins is their localization to the primary cilium, a specialized sensory organelle critical for signaling.
The founding members of this family, PKD1 and PKD2, are evolutionarily conserved from worms to humans and play an indispensable role in development and survival, as homozygous deletion of either gene results in early embryonic lethality. In contrast, heterozygous mutations give rise to Autosomal Dominant Polycystic Kidney Disease (ADPKD), one of the most common inherited disorders, affecting approximately 12 million individuals worldwide. ADPKD is characterized by the progressive formation of large fluid-filled cysts, leading to profound architectural disruption of the kidney and ultimately to end-stage renal failure.
Over the past twenty-five years, my group has focused on several fundamental questions: What is the molecular function of the PKD1/PKD2 complex—does it operate as an ion channel, a GPCR, or a hybrid of both? What extracellular stimuli activate this receptor/channel complex? What downstream signaling pathways are engaged upon activation? And what is the precise role of the primary cilium in mediating PKD1/PKD2-dependent signaling? Through a combination of biophysical, biochemical, cell biological, and genetic approaches, we have elucidated key mechanisms governing the function and regulation of these proteins.
In 2016, we identified secreted WNT proteins as activating ligands for the Polycystin complex (PKD1/PKD2), thereby defining this complex as a previously unrecognized class of WNT receptors. More recent work has demonstrated that the PKD1/PKD2 complex functions as a WNT-activated GPCR that signals through a subset of Gα subunits, ultimately leading to the inhibition of cAMP production. Notably, abnormally elevated cAMP levels within cells and cilia have been strongly implicated in cystogenesis. Currently, we are investigating how the disruption of the PKD1/PKD2 signaling properties of this complex leads to cyst formation.
In parallel, we have investigated the role of the Polycystin complex in ciliary structure and function. Our studies reveal that loss of Polycystin function impairs the normal process of ciliary disassembly. This defect results in abnormally elongated cilia as cells re-enter the cell cycle. Given that cilia-based signaling is tightly coordinated with cell cycle progression, structural abnormalities are likely to disrupt the precise timing of signaling events. We are currently investigating whether prolonged cilia-based signaling leads to changes in cell cycle progression and dedifferentiation, often reported in cystic cells.
Select Publications:
- Hardy EP, Haider AN, Patel MM, Nesin V, Hoang HTM, Gostynska SE, Berry WL, Pioszak AA, Ahmad M, Parnell SC, Tsiokas L. A heteromeric TRP channel that functions as a WNT-activated G protein-coupled receptor. Nature Communications 17(1): 3233, 2026.
- Patel MM, Gerakopoulos V, Lettenmaier B, Petsouki E, Zimmerman KA, Sayer JA, Tsiokas L. SOX9-dependent fibrosis drives renal function in nephronophthisis. EMBO Molecular Medicine 17(6):1238-1258, 2025.
- Petsouki E, Gerakopoulos V, Szeto N, Chang W, Humphrey MB, Tsiokas L. FBW7 couples structural integrity and fucntional output of primary cilia. Communications Biology 4(1):1066, 2021.
- Gerakopoulos V, Ngo P, Tsiokas L. Loss of polycystins suppresses deciliation via the activation of the centrosomal integrity pathway. Life Science Alliance. 3(9):e202000750, 2020.
- Kim S., Nie H., Nesin V., Tran U., Outeda P., Bai C-X., Keeling J., Maskey M., Watnick T., Wessely O., Tsiokas L. The Polycystin complex mediates WNT/Ca2+ signaling. Nature Cell Biology, 18(7):752-64, 2016.
http://www.nature.com/nrneph/journal/v12/n7/pdf/nrneph.2016.77.pdf
http://f1000.com/prime/726375187
- Maskey D., Marlin MC, Kim S, Kim S, Ong EC, Li G, and Tsiokas L. Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length. The EMBO Journal, 34(19):2424-40, 2015. PMCID4601663 (available on 2016-10-01)
News & Views: http://emboj.embopress.org/content/embojnl/34/19/2388.full.pdf
- Nesin V, Wiley G, Kousi M, Ong EC, Lehmann T, Nicholl DJ, Suri M, Shahrizaila N, Katsanis N, Gaffney PM, Wierenga KJ, Tsiokas L. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proceedings of the National Academy of Sciences (USA), 111(11): 4197-202, 2014.
- Kim S., Zaghloul NA., Bubenshchikova E., Oh EC., Rankin S., Katsanis N., Obara T., and Tsiokas L. Nde-1 mediated suppression of ciliogenesis affects cell cycle re-entry. Nature Cell Biology, 13(4): 351-60, 2011.
“New and Views” http://www.nature.com/ncb/journal/v13/n4/pdf/ncb0411-340.pdf
- Bai CX., Kim S., Li WP., Streets AJ., Ong AC., and Tsiokas L. Activation of TRPP2 through mDia1-dependent voltage gating. EMBO Journal, 27: 1345-1356, 2008.
- Bai CX., Giamarchi A., Rodat-Despoix L., Padilla F., Downs T., Tsiokas L.* and Delmas P.* Formation of a novel receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Reports, 9:472-9, 2008 *Corresponding authors
For a complete list of publications: https://pubmed.ncbi.nlm.nih.gov/?term=tsiokas&sort=date