Protocadherin-7 Regulates Osteoclast Differentiation through Intracellular SET-Binding Domain-Mediated RhoA and Rac1 Activation.

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  • Author(s): Kim H;Kim H; Takegahara N; Takegahara N; Choi Y; Choi Y
  • Source:
    International journal of molecular sciences [Int J Mol Sci] 2021 Dec 04; Vol. 22 (23). Date of Electronic Publication: 2021 Dec 04.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Cell Differentiation/*physiology ; Neuropeptides/*metabolism ; Osteoclasts/*cytology ; Protocadherins/*metabolism ; rac1 GTP-Binding Protein/*metabolism ; rhoA GTP-Binding Protein/*metabolism; Animals ; Binding Sites ; Cells, Cultured ; Mice, Mutant Strains ; Osteoclasts/metabolism ; Protein Domains ; Protocadherins/genetics ; Mice
    • 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.
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    • Grant Information:
      R01 AR077526 United States AR NIAMS NIH HHS; AR077526 United States AR NIAMS NIH HHS
    • Contributed Indexing:
      Keywords: Pcdh7; Rac1; RhoA; SET; differentiation; osteoclast
    • Accession Number:
      0 (Neuropeptides)
      0 (PCDH7 protein, mouse)
      0 (Protocadherins)
      0 (Rac1 protein, mouse)
      EC 3.6.5.2 (RhoA protein, mouse)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
      EC 3.6.5.2 (rhoA GTP-Binding Protein)
    • Publication Date:
      Date Created: 20211210 Date Completed: 20220107 Latest Revision: 20240226
    • Publication Date:
      20240226
    • Accession Number:
      PMC8658210
    • Accession Number:
      10.3390/ijms222313117
    • Accession Number:
      34884920