TY - JOUR
T1 - Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses
AU - Sharma, Bhumika
AU - Joshi, Sonali
AU - Sassano, Antonella
AU - Majchrzak, Beata
AU - Kaur, Surinder
AU - Aggarwal, Priya
AU - Nabet, Behnam
AU - Bulic, Marinka
AU - Stein, Brady L.
AU - McMahon, Brandon
AU - Baker, Darren P.
AU - Fukunaga, Rikiro
AU - Altman, Jessica K.
AU - Licht, Jonathan D.
AU - Fish, Eleanor N.
AU - Platanias, Leonidas C.
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871295536&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871295536&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.400721
DO - 10.1074/jbc.M112.400721
M3 - Article
C2 - 23074222
AN - SCOPUS:84871295536
VL - 287
SP - 42352
EP - 42360
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 50
ER -