Abstract
Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Although the cell-intrinsic role of Pcdh7 in osteoclast differentiation has been demonstrated, the molecular mechanisms of Pcdh7 regulating osteoclast differentiation remain to be determined. Here, we demonstrate that Pcdh7 contributes to osteoclast differentiation by regulating small GTPases, RhoA and Rac1, through its SET oncoprotein binding domain. Pcdh7 is associated with SET along with RhoA and Rac1 during osteoclast differentiation. Pcdh7-deficient (Pcdh7−/−) cells showed abolished RANKL-induced RhoA and Rac1 activation, and impaired osteoclast differentiation. Impaired osteoclast differentiation in Pcdh7−/− cells was restored by retroviral transduction of full-length Pcdh7 but not by a Pcdh7 mutant that lacks SET binding domain. The direct crosslink of the Pcdh7 intracellular region induced the activation of RhoA and Rac1, which was not observed when Pcdh7 lacks the SET binding domain. Additionally, retroviral transduction of the constitutively active form of RhoA and Rac1 completely restored the impaired osteoclast differentiation in Pcdh7−/− cells. Collectively, these results demonstrate that Pcdh7 controls osteoclast differentiation by regulating RhoA and Rac1 activation through the SET binding domain.
Highlights
Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherins, which comprise another phylogenetically distinct group of the cadherin superfamily [1]
It has been reported that association with SET is important for the function of Pcdh7, prompting us to determine whether the association of Pcdh7 with SET is detected during osteoclast differentiation
Pcdh7 is associated with RhoA and Rac1 but not Cdc42 (Figure 1). These results suggested the involvement of SET and small GTPases RhoA and Rac1 in Pcdh7-mediated osteoclast differentiation
Summary
Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherins, which comprise another phylogenetically distinct group of the cadherin superfamily [1]. Pcdh encodes an integral membrane protein and is thought to function in cell–cell recognition and adhesion through homophilic binding [9], and in the regulation of cell signaling through its interaction with intracellular signaling proteins such as oncoprotein SET/Template-activating factor 1 (TAF1) and protein phosphatase-1α (PP1α) through the cytoplasmic domain [6,8,11,12,13]. Osteoclasts are specialized multinucleated giant cells that resorb bone [15,16]. These cells are hematopoietic in origin and are derived from myeloid precursors. The Rho family small GTPases including RhoA, Rac, and Cdc, are key regulators of actin dynamics and have critical roles in osteoclast biology [25,26]
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