Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses.
Interferons (IFNs) have important antiviral and antineoplastic properties, but the precise mechanisms required for generation of these responses remain to be defined. We provide evidence that during engagement of the Type I IFN receptor (IFNR), there is up-regulation of expression of Sprouty (Spry) proteins 1, 2, and 4. Our studies demonstrate that IFN-inducible up-regulation of Spry proteins is Mnk kinase-dependent and results in suppressive effects on the IFN-activated p38 MAP kinase (MAPK), the function of which is required for transcription of interferon-stimulated genes (ISGs). Our data establish that ISG15 mRNA expression and IFN-dependent antiviral responses are enhanced in Spry1,2,4 triple knock-out mouse embryonic fibroblasts, consistent with negative feedback regulatory roles for Spry proteins in IFN-mediated signaling. In other studies, we found that siRNA-mediated knockdown of Spry1, Spry2, or Spry4 promotes IFN-inducible antileukemic effects in vitro and results in enhanced suppressive effects on malignant hematopoietic progenitors from patients with polycythemia vera. Altogether, our findings demonstrate that Spry proteins are potent regulators of Type I IFN signaling and negatively control induction of Type I IFN-mediated biological responses.
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Bhumika
B
Sharma
Sonali
S
Joshi
Antonella
A
Sassano
Beata
B
Majchrzak
Surinder
S
Kaur
Priya
P
Aggarwal
Behnam
B
Nabet
Marinka
M
Bulic
Brady L
BL
Stein
Brandon
B
McMahon
Darren P
DP
Baker
Rikiro
R
Fukunaga
Jessica K
JK
Altman
Jonathan D
JD
Licht
Eleanor N
EN
Fish
Leonidas C
LC
Platanias
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C486055:SPRY1 protein, human; C485561:SPRY2 protein, human; C499038:SPRY4 protein, human; C425468:Spry1 protein, mouse; C499037:Spry4 protein, mouse; D053633:Receptor, Interferon alpha-beta; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases