Publications

2025

Synthetic G protein-coupled receptors for programmable sensing and control of cell behaviour
Kalogriopoulos NA*, Tei R*, Yan Y, Klein PM, Ravalin M, Cai B, Soltesz I, Li Y, Ting AY.
Nature. (2025)  637(8044):230-239.
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Synthetic receptors that mediate antigen-dependent cell responses are transforming therapeutics, drug discovery and basic research. However, established technologies such as chimeric antigen receptors can only detect immobilized antigens, have limited output scope and lack built-in drug control. Here we engineer synthetic G-protein-coupled receptors (GPCRs) that are capable of driving a wide range of native or non-native cellular processes in response to a user-defined antigen. We achieve modular antigen gating by engineering and fusing a conditional auto-inhibitory domain onto GPCR scaffolds. Antigen binding to a fused nanobody relieves auto-inhibition and enables receptor activation by drug, thus generating programmable antigen-gated G-protein-coupled engineered receptors (PAGERs). We create PAGERs that are responsive to more than a dozen biologically and therapeutically important soluble and cell-surface antigens in a single step from corresponding nanobody binders. Different PAGER scaffolds allow antigen binding to drive transgene expression, real-time fluorescence or endogenous G-protein activation, enabling control of diverse cellular functions. We demonstrate multiple applications of PAGER, including induction of T cell migration along a soluble antigen gradient, control of macrophage differentiation, secretion of therapeutic antibodies and inhibition of neuronal activity in mouse brain slices. Owing to its modular design and generalizability, we expect PAGERs to have broad utility in discovery and translational science.

Earlier than 2025

A light-gated transcriptional recorder for detecting cell-cell contacts
Cho KF, Gillespie SM, Kalogriopoulos NA, Quezada MA, Jacko M, Monje M, Ting AY
Elife. (2022)  21(1):e70881.
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Receptor tyrosine kinases activate heterotrimeric G proteins by phosphorylating within the interdomain cleft of Gαi
Kalogriopoulos NA, Lopez-Sanchez I, Lin C, Ngo T, Midde K, Aznar N, Murray F, Garcia-Marcos M, Kufareva I, Ghassemian M, Ghosh P
Proc Natl Acad Sci. (2020)  117(46):28763-28774.
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GIV•Kindlin interaction is required for kindlin-mediated integrin recognition and activation
Rohena C*, Kalogriopoulos NA*, Rajapakse N, Roy S, Lopez-Sanchez I, Ablack J, Sahoo D, Ghosh P
iScience. (2020)  26;23(6):101209.
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Structural basis for GPCR-independent activation of heterotrimeric Gi proteins
Kalogriopoulos NA*, Rees SD*, Ngo T, Kopcho N, Ilatovskiy A, Sun N, Komives E, Chang G, Ghosh P, Kufareva I
Proc Natl Acad Sci. (2019)  116(33):16394-16403.
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Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple
Aznar N, Ear J, Dunkel Y, Sun N, Satterfield K, He F, Kalogriopoulos NA, Lopez-Sanchez I, Ghassemian M, Sahoo D, Kufareva I, Ghosh P
Sci Signal. (2018)  11(519).
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[PROTOCOLS] Biochemical, Biophysical and Cellular Techniques to Study the Guanine Nucleotide Exchange Factor, GIV/Girdin
Ghosh P, Aznar N, Swanson L, Lo IC, Lopez-Sanchez I, Ear J, Rohena C, Kalogriopoulos NA, Joosen L, Dunkel Y, Sun N, Nguyen P, Bhandari D
Curr Protoc Chem Biol. (2016)  8:265-298.
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[REVIEW] Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time
Aznar N, Kalogriopoulos NA, Midde K, Ghosh P
Bioessays. (2016)  38:379-93.
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GIV/girdin binds exocyst subunit-Exo70 and regulates exocytosis of GLUT4 storage vesicles
Lopez-Sanchez I, Ma GS, Pedram S, Kalogriopoulos NA, Ghosh P
Biochem Biophys Res Commun. (2015)  468:287-93.
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Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins
Lopez-Sanchez I, Kalogriopoulos NA, Lo I, Kabir F, Midde K, Wang H, Ghosh P
Mol Biol Cell. (2015)  26:4313-24.
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Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
Ma G, Lopez-Sanchez I, Aznar N, Kalogriopoulos NA, Pedram S, Midde K, Ciaraldi T, Henry RR, Ghosh P
Mol Biol Cell. (2015)  26:4209-23.
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Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors
Ma G, Aznar N, Kalogriopoulos NA, Midde K, Lopez-Sanchez I, Sato E, Dunkel Y, Gallo R, Ghosh P
Proc Natl Acad Sci. (2015)  112:E2602-10
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Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the Hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival
Yang RK, Kalogriopoulos NA, Rakhmilevich AL, Ranheim EA, Seo S, Kim K, Alderson KL, Gan J, Reisfeld RA, Gillies SD, Hank JA, Sondel PM
Cancer Immunol Immunother. (2013)  62:1303-13
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Intratumoral hu14.18-IL2 (IC) Induces Local and Systemic Antitumor Effects that Involve Both Activated T- and NK cells as well as Enhanced IC Retention
Yang RK*, Kalogriopoulos NA*, Rakhmilevich AL, Ranheim EA, Seo S, Alderson KL, Gan J, Hank JA, Sondel PM
J Immunol. (2012)  189:2656-64.
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Tumor-associated myeloid cells can be activated in vitro and in vivo to mediate antitumor effects
Rakhmilevich A, Van de Voort T, Baldeshwiler M, Felder M, Yang RK, Kalogriopoulos NA, Koslov D, Sondel PM
Cancer Immunol Immunother. (2012)  61:1683-97.
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