TY - JOUR
T1 - Tetraspanin microdomains control localized protein kinase C signaling in B cells
AU - Zuidscherwoude, Malou
AU - Dunlock, Vera Marie E.
AU - Van Den Bogaart, Geert
AU - Van Deventer, Sjoerd J.
AU - Van Der Schaaf, Alie
AU - Van Oostrum, Jenny
AU - Goedhart, Joachim
AU - In't Hout, Joanna
AU - Hämmerling, Günter J.
AU - Tanaka, Satoshi
AU - Nadler, André
AU - Schultz, Carsten
AU - Wright, Mark D.
AU - Adjobo-Hermans, Merel J.W.
AU - Van Spriel, Annemiek B.
N1 - Funding Information:
This work was supported by the Netherlands Organisation for Scientific Research (NWO-ALW VIDI grant 864.11.006 to A.B.v.S.), the Dutch Cancer Society (KUN2014-6845 to A.B.v.S.), and the Radboudumc (PhD grant to M.Z.). G.v.d.B. is funded by a fellowship from the Radboudumc, the Human Frontier Science Program, and the European Research Council (Starting Grant 336479). A.B.v.S. was awarded a European Research Council Consolidator Grant (Secret Surface, 724281). C.S. was funded by Deutsche Forschungsgemeinschaft (TRR83).
Publisher Copyright:
© The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017/5/9
Y1 - 2017/5/9
N2 - Activation of B cells by the binding of antigens to the B cell receptor (BCR) requires the protein kinase C (PKC) family member PKCβ. Because PKCs must translocate to the plasma membrane to become activated, we investigated the mechanisms regulating their spatial distribution in mouse and human B cells. Through live-cell imaging, we showed that BCR-stimulated production of the second messenger diacylglycerol (DAG) resulted in the translocation of PKCβ from the cytosol to plasma membrane regions containing the tetraspanin protein CD53. CD53 was specifically enriched at sites of BCR signaling, suggesting that BCR-dependent PKC signaling was initiated at these tetraspanin microdomains. Fluorescence lifetime imaging microscopy studies confirmed the molecular recruitment of PKC to CD53-containing microdomains, which required the amino terminus of CD53. Furthermore, we showed that Cd53-deficient B cells were defective in the phosphorylation of PKC substrates. Consistent with this finding, PKC recruitment to the plasma membrane was impaired in both mouse and human CD53-deficient B cells compared to that in their wild-type counterparts. These data suggest that CD53 promotes BCR-dependent PKC signaling by recruiting PKC to the plasma membrane so that it can phosphorylate its substrates and that tetraspanin-containing microdomains can act as signaling hotspots in the plasma membrane. 2017
AB - Activation of B cells by the binding of antigens to the B cell receptor (BCR) requires the protein kinase C (PKC) family member PKCβ. Because PKCs must translocate to the plasma membrane to become activated, we investigated the mechanisms regulating their spatial distribution in mouse and human B cells. Through live-cell imaging, we showed that BCR-stimulated production of the second messenger diacylglycerol (DAG) resulted in the translocation of PKCβ from the cytosol to plasma membrane regions containing the tetraspanin protein CD53. CD53 was specifically enriched at sites of BCR signaling, suggesting that BCR-dependent PKC signaling was initiated at these tetraspanin microdomains. Fluorescence lifetime imaging microscopy studies confirmed the molecular recruitment of PKC to CD53-containing microdomains, which required the amino terminus of CD53. Furthermore, we showed that Cd53-deficient B cells were defective in the phosphorylation of PKC substrates. Consistent with this finding, PKC recruitment to the plasma membrane was impaired in both mouse and human CD53-deficient B cells compared to that in their wild-type counterparts. These data suggest that CD53 promotes BCR-dependent PKC signaling by recruiting PKC to the plasma membrane so that it can phosphorylate its substrates and that tetraspanin-containing microdomains can act as signaling hotspots in the plasma membrane. 2017
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U2 - 10.1126/scisignal.aag2755
DO - 10.1126/scisignal.aag2755
M3 - Article
C2 - 28487417
AN - SCOPUS:85019235321
VL - 10
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 478
M1 - aag2755
ER -