TY - JOUR
T1 - STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex
AU - Jeong, Eutteum
AU - Choi, Han Kyoung
AU - Park, Jin Hee
AU - Lee, Soo Young
N1 - Funding Information:
Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (No. 2016R1A2B3010699; No. 2012R1A5A1048236).
Publisher Copyright:
© 2018, ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - The receptor activator of nuclear factor-κB (RANK) protein activates various protein kinase signaling cascades, including those involving NF-κB, mitogen-activated protein kinase (MAPK), and Bruton tyrosine kinase (Btk)/tyrosine-protein kinase Tec. However, the mechanism underlying the negative regulation of RANK by downstream signaling molecules remains unclear. Here, we report that Src homology 3 domain and cysteine-rich domain-containing protein 2 (STAC2) is a novel RANK ligand-inducible protein that negatively regulates RANK-mediated osteoclast formation. STAC2 physically interacts with RANK and inhibits the formation of the RANK signaling complex, which contains Grb-2-associated binder 2 (Gab2) and phospholipase Cγ2 (PLCγ2), thus leading to the suppression of RANK-mediated NF-κB and MAPK activation. Furthermore, STAC2 overexpression limits Btk/Tec-mediated PLCγ2 phosphorylation via the interaction between STAC2 and Btk/Tec. Taken together, our results reveal a novel mechanism whereby RANK signaling is restricted by its physical interaction with STAC2.
AB - The receptor activator of nuclear factor-κB (RANK) protein activates various protein kinase signaling cascades, including those involving NF-κB, mitogen-activated protein kinase (MAPK), and Bruton tyrosine kinase (Btk)/tyrosine-protein kinase Tec. However, the mechanism underlying the negative regulation of RANK by downstream signaling molecules remains unclear. Here, we report that Src homology 3 domain and cysteine-rich domain-containing protein 2 (STAC2) is a novel RANK ligand-inducible protein that negatively regulates RANK-mediated osteoclast formation. STAC2 physically interacts with RANK and inhibits the formation of the RANK signaling complex, which contains Grb-2-associated binder 2 (Gab2) and phospholipase Cγ2 (PLCγ2), thus leading to the suppression of RANK-mediated NF-κB and MAPK activation. Furthermore, STAC2 overexpression limits Btk/Tec-mediated PLCγ2 phosphorylation via the interaction between STAC2 and Btk/Tec. Taken together, our results reveal a novel mechanism whereby RANK signaling is restricted by its physical interaction with STAC2.
UR - http://www.scopus.com/inward/record.url?scp=85040653203&partnerID=8YFLogxK
U2 - 10.1038/s41418-017-0048-5
DO - 10.1038/s41418-017-0048-5
M3 - Article
C2 - 29348675
AN - SCOPUS:85040653203
SN - 1350-9047
VL - 25
SP - 1364
EP - 1374
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 8
ER -