Receptor activator of NF-κB (RANK) cytoplasmic motif, 369PFQEP373, plays a predominant role in osteoclast survival in part by activating Akt/PKB and its downstream effector AFX/FOXO4

Academic Article

Abstract

  • Receptor activator of NF-κB ligand (RANKL) plays a crucial role in osteoclast differentiation, function, and survival. RANKL exerts its effect by activating its receptor RANK (receptor activator of NF-κB), which recruits various intracellular signaling molecules via specific motifs in its cytoplasmic tail. Previously, we identified three RANK cytoplasmic motifs (Motif 1, PFQEP ; Motif 2, PVQEET ; and Motif 3, PVQEQG ) mediating osteoclast formation and function. Here, we investigated RANK cytoplasmic motifs involved in osteoclast survival. Motif 1, in contrast to its minimal role in osteoclast formation and function, plays a predominant role in promoting osteoclast survival. Moreover, whereas Motif 2 and Motif 3 are highly potent in osteoclast formation and function, they exert a moderate effect on osteoclast survival. We also investigated the role of these motifs in activating Akt/protein kinase B (PKB), which has been implicated in RANKL-induced osteoclast survival. Motif 1, but not Motif 2 or Motif 3, is able to stimulate Akt/PKB activation. Because Akt/PKB has been shown to utilize distinct downstream effectors (glycogen synthase kinase-3β, FKHR/FOXO1a, BAD, and AFX/FOXO4) to regulate cell survival, we next determined which downstream effector(s) is activated by Akt/PKB to promote osteoclast survival. Our data revealed that RANKL only stimulates AFX/FOXO4 phosphorylation, indicating that AFX/FOXO4 is a key downstream target activated by Akt/PKB to modulate osteoclast survival. Taken together, we conclude that Motif 1 plays a predominant role in mediating osteoclast survival in part by activating Akt/PKB and its downstream effector AFX/FOXO4. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. 369 373 559 564 604 609
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Liu W; Wang S; Wei S; Sun L; Feng X
  • Start Page

  • 43064
  • End Page

  • 43072
  • Volume

  • 280
  • Issue

  • 52