TY - JOUR
T1 - Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma
AU - Qu, Changju
AU - Liu, Yadong
AU - Kunkalla, Kranthi
AU - Singh, Rajesh R.
AU - Blonska, Marzenna
AU - Lin, Xin
AU - Agarwal, Nitin Kumar
AU - Vega, Francisco
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/6/6
Y1 - 2013/6/6
N2 - Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-kB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gai and Ga12 to activate PKCb/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.
AB - Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-kB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gai and Ga12 to activate PKCb/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.
UR - http://www.scopus.com/inward/record.url?scp=84881082520&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881082520&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-12-470153
DO - 10.1182/blood-2012-12-470153
M3 - Article
C2 - 23632891
AN - SCOPUS:84881082520
SN - 0006-4971
VL - 121
SP - 4718
EP - 4728
JO - Blood
JF - Blood
IS - 23
ER -