Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers

ELife
Ignacio MoragaK Christopher Garcia

Abstract

Cytokine and growth-factor ligands typically signal through homo- or hetero-dimeric cell surface receptors via Janus Kinase (JAK/TYK), or Receptor Tyrosine Kinase (RTK)-mediated trans-phosphorylation. However, the number of receptor dimer pairings occurring in nature is limited to those driven by natural ligands encoded within our genome. We have engineered synthethic cytokines (synthekines) that drive formation of cytokine receptor dimer pairings that are not formed by endogenous cytokines and that are not found in nature, and which activate distinct signaling programs. We show that a wide range of non-natural cytokine receptor hetero-dimers are competent to elicit a signaling output. We engineered synthekine ligands that assembled IL-2Rβ/IL-4Rα or IL-4Rα/IFNAR2 receptor heterodimers, that do not occur naturally, triggering signaling and functional responses distinct from those activated by the endogenous cytokines IL-2, IL-4, and IFN. Furthermore, hybrid synthekine ligands that dimerized a JAK/STAT cytokine receptor with a receptor tyrosine kinase (RTK) also elicited a signaling response. Synthekines represent a new family of synthetic ligands with pre-defined receptors, but 'orphan' functions, that enable the full combinator...Continue Reading

References

Apr 20, 1990·Cell·A Ullrich, J Schlessinger
Oct 1, 1990·Immunology Today·J F Bazan
Jan 4, 1994·Proceedings of the National Academy of Sciences of the United States of America·H OhashiA Yoshimura
Jan 1, 1995·Annual Review of Immunology·J N IhleO Silvennoinen
Jan 1, 1993·Annual Review of Biophysics and Biomolecular Structure·J A Wells, A M de Vos
Nov 1, 1995·Trends in Biochemical Sciences·Z Songyang, L C Cantley
Sep 5, 2002·Nature Reviews. Molecular Cell Biology·David E Levy, J E Darnell
Mar 5, 2003·BioTechniques·A I SaeedJ Quackenbush
Sep 25, 2003·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Peter O Krutzik, Garry P Nolan
May 6, 2004·Science's STKE : Signal Transduction Knowledge Environment·Robert M Stroud, James A Wells
May 7, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·M Nusrat SharifLionel B Ivashkiv
Sep 1, 1993·Current Biology : CB·J F Bazan
Feb 3, 2005·Proceedings of the National Academy of Sciences of the United States of America·Sherry L LaporteRobert M Stroud
Apr 15, 2006·The Journal of Endocrinology·Mark O HuisingGert Flik
Jun 6, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Allison-Lynn AndrewsDonna E Davies
Feb 22, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Peter J Murray
Jun 8, 2007·Blood·Thomas JahnKenneth Weinberg
Dec 1, 2007·Nature Reviews. Drug Discovery·Ernest C BordenGeorge R Stark
Sep 27, 2008·Annual Review of Immunology·Xinquan WangK Christopher Garcia
Nov 13, 2008·Cytotechnology·Masahiro KawaharaTeruyuki Nagamune
Jul 1, 2009·Molecular and Cellular Biology·Ignacio MoragaSandra Pellegrini
Mar 3, 2010·Annual Review of Immunology·Jinfang ZhuWilliam E Paul
Jul 7, 2010·Cell·Mark A Lemmon, Joseph Schlessinger
Oct 20, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anette H H van Boxel-DezaireGeorge R Stark
Aug 20, 2011·Current Opinion in Immunology·Greg M DelgoffeDario A A Vignali
Oct 30, 2012·Nature Chemical Biology·Ilkka S JunttilaK Christopher Garcia
Oct 2, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yuxin WangGeorge R Stark
Jan 7, 2014·Advances in Immunology·Ignacio MoragaK Christopher Garcia
May 29, 2014·Science Signaling·Doron LevinGideon Schreiber
Dec 11, 2014·Annual Review of Immunology·Jamie B SpanglerK Christopher Garcia

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Citations

May 24, 2018·Nature Communications·Erika EngelowskiJürgen Scheller
May 29, 2019·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Jung-Hyun ParkCarmen Molina-París
Sep 13, 2019·Nature Communications·Susanne MeierMatthias J Feige
Mar 1, 2019·Nature·Juan L MendozaK Christopher Garcia
May 13, 2017·ELife·Alejandro Villarino, John J O'Shea
Oct 16, 2018·Frontiers in Immunology·Claire GorbyIgnacio Moraga
Jan 11, 2019·Nature·Daniel-Adriano SilvaDavid Baker
Aug 8, 2019·The Journal of Biological Chemistry·Jamie B SpanglerK Christopher Garcia
Aug 28, 2020·Frontiers in Immunology·Iva Marković, Savvas N Savvides
Nov 28, 2020·Science·Aileen W Li, Wendell A Lim
Feb 9, 2021·Advanced Science·Benjamin A YangCarlos A Aguilar
Feb 26, 2019·Current Opinion in Biotechnology·Patrick J KrohlJamie B Spangler
Apr 4, 2021·Cancer Discovery·Antoni Ribas
Apr 14, 2021·Cell·Zibo Chen, Michael B Elowitz
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Judith PradoNiels Eijkelkamp
Sep 17, 2021·Scientific Reports·Ravindra KumarRoselyne Castonguay

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
flow cytometry
transfection
size exclusion chromatography
PCR

Software Mentioned

FlowJo
TM4
GraphPad Prism

Related Concepts

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Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

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