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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.

STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex