Membrane Rafts Play a Crucial Role in Receptor Activator of Nuclear Factor κB Signaling and Osteoclast Function

Ha, Hyunil; Kwak, Han Bok; Lee, Seung Ku; Na, Doe Sun; Rudd, Christopher E.; Lee, Zang Hee; Kim, Hong-Hee

doi:10.1074/jbc.m212626200

Cited by 83 publications

(73 citation statements)

References 49 publications

(60 reference statements)

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“…Furthermore, raft-disrupting agents destroyed the integrity of actin-ring structure, boneresorbing activity, and survival of osteoclasts. However, raft disruption did not impaired MAPK and NF-κB activation by RANKL (Ha et al, 2003). In this study, we demonstrated that the majority of the overexpressed RANK was localized in lipid rafts portion (Figure 1).…”

Section: Discussionmentioning

confidence: 59%

Lipid rafts are important for the association of RANK and TRAF6

Kwak²,

Le³

et al. 2003

Exp Mol Med

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A bstractRafts, cholesterol-and sphingolipid-rich m em brane m icrodom ains, have been show n to play an important role in im m une cell activation. M ore recently rafts w ere im plicated in the signal transduction by m em bers of the TNF receptor (TNFR) fam ily. In this study, we provide evidences that the raft m icrodom ain has a crucial role in RANK (receptor activator of NF-κB) signaling. W e found that the m ajority of the ectopically expressed RANK and substantial portion of endogenous TRAF2 and TRAF6 w ere detected in the low -density raft fractions. In addition, TRAF6 association w ith rafts was increased by RANKL stim ulation. The disruption of rafts blocked the TRAF6 translocation by RANK ligand and im peded the interaction betw een RANK and TRAF6. O ur observations dem onstrate that proper RANK signaling requires the function of raft m em brane m icrodom ains.

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Section: Discussionmentioning

confidence: 59%

Lipid rafts are important for the association of RANK and TRAF6

Kwak²,

Le³

et al. 2003

Exp Mol Med

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“…On the other hand, TRAF6 has been shown to translocate to lipid rafts in osteoclasts upon activation of another TNF-R family member, the receptor activator of nuclear factor kB (RANK). In addition, the TRAF-6 translocation following RANK engagement was accompanied by Akt activation, a phenomenon inhibited by lipid raft disruption [46]. Therefore, in our study, CD40-mediated PI-3K activation might be dependent on lipid rafts translocation due to the type of TRAF upstream of its signaling.…”

mentioning

confidence: 56%

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

et al. 2011

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CanadaCD40, a member of the TNF receptor family, is expressed on a variety of immune and nonimmune cells. Its interaction with its ligand, CD154, plays a pivotal role in humoral and cellmediated immunity. A low level of CD40 is constitutively associated within membrane lipid rafts and, upon engagement, this level is significantly enhanced. In this study, our objective is to evaluate the process of CD40/lipid raft association in terms of the signals required for its initiation and the resulting biological outcomes. Here, we show the CD40/lipid raft association to be independent of PI-3-kinase, Src family kinases and p38 MAPK pathways. Moreover, CD40 lacking its intracellular domain, which is usually required for CD40-mediated signaling, still localizes to lipid rafts upon engagement, confirming that the CD40/ lipid raft association is independent of signaling events. As to the biological outcomes of the CD40/lipid raft association, we show that disrupting lipid raft integrity selectively abolishes CD40-mediated Akt phosphorylation. In addition, replacing the transmembrane domain of CD40 with that of CD45 (a protein excluded from lipid rafts) dramatically reduced CD40-mediated Akt phosphorylation and B7.1 upregulation, while not influencing p38, ERK and JNK activation. Together, these findings clarify the requirements for CD40/lipid raft association and the signals triggered upon CD40 engagement by CD154.Keywords: CD40 . Lipid rafts . Signaling . Transmembrane domain Supporting Information available online IntroductionInteraction between the TNFR, CD40 and its ligand CD154 drives crucial steps in humoral immune responses [1][2][3]. Notably, the CD40/CD154 interaction is critical for the affinity maturation of immunoglobulins (Ig), the development of long-lived plasma B cells and the clonal expansion of memory B cells [1,4,5]. In the absence of intrinsic tyrosine kinase activity, CD40 transmits its intracellular signal via recruitment of several adaptor proteins, such as JAK3 [6] and TNFR-associated factor (TRAF) proteins [5], to specific domains in the CD40 cytoplasmic tail [4,[7][8][9]. This results in the activation of members of the Src kinase family (such as Lyn and Fyn), and other protein tyrosine kinases (such as Syk and Btk) [10,11]; the activation of PI-3 kinase and phospholipase Cg2 [11] and the activation of the MAP kinases p38, JNK and ERK [12][13][14].Lipid rafts are detergent-resistant plasma membrane microdomains that are enriched in cholesterol and sphingolipids. Being 2358scaffolds of many signaling effectors including lipid-anchored proteins (such as Thy-1 and alkaline phosphatase) and signaling molecules (such as some Src kinase family members), lipid rafts act as platforms to initiate and regulate signal transduction processes in many cellular models [15,16]. Engagement of CD40 molecules leads to CD40 clustering into ceramide-enriched lipid rafts of living human B cells [17,18]. Common early events following CD40 clustering in mouse B cells [19] and in human dendritic cells [20] include Lyn act...

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“…Moreover, EEIG1 could associate with Tec/Btk but not Syk. Further, we observed that after RANKL stimulation, EEIG1, Gab2, Btk, as well as RANK, were recruited to membrane lipid rafts ( Figure 6J), which are crucial signaling domains for RANK signal transduction [29,30]. Thus, it is likely that the RANK signaling complex generated upon RANKL stimulation contributes to the RANK-mediated osteoclastogenic signaling.…”

Section: Han Kyoung Choi Et Al 531mentioning

confidence: 75%

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

et al. 2013

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The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.

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Membrane Rafts Play a Crucial Role in Receptor Activator of Nuclear Factor κB Signaling and Osteoclast Function

Cited by 83 publications

References 49 publications

Lipid rafts are important for the association of RANK and TRAF6

Lipid rafts are important for the association of RANK and TRAF6

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

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