Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Decker, Corinne E.; Hesker, Pamela R.; Zhang, Kaihua; Faccio, Roberta

doi:10.1074/jbc.m113.477281

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…The role of the PLCγ isoenzyme in bone resorption and in adhesion receptor signalling of osteoclasts was further emphasized in a recent review reinforcing the statements made by Kertész et al., . Moreover, Dr. Faccio's group provided genetic evidence that targeting PLCγ2 can suppress inflammatory osteolysis . This is in contrast with our observation that PLCγ2 does not play a major role in ovariectomy‐induced bone loss, indicating that inflammatory osteolysis and oestrogen deficiency–triggered bone resorption may utilize different signalling pathways.…”

Section: Phospholipase Cγ2 Is Required For Basal But Not Oestrogen Desupporting

confidence: 84%

Research update for articles published in EJCI in 2012

Dullaart

Al-Daghri

Ashina

et al. 2014

Eur J Clin Investigation

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Section: Phospholipase Cγ2 Is Required For Basal But Not Oestrogen Desupporting

confidence: 84%

Research update for articles published in EJCI in 2012

Dullaart

Al-Daghri

Ashina

et al. 2014

Eur J Clin Investigation

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“…However, an inhibitor that would specifically target the interaction between K15 and PLCγ1, without interfering with the physiological functions of PLCγ1 might counteract only KSHV-dependent signalling processes. Since Decker et al [ 45 ] successfully impaired pathological osteolysis by uncoupling the adaptor and the catalytical functions of PLCγ2 by ectopic expression of tandem PLCγ2 SH2 domains, we used a similar approach and tested the PLCγ2 cSH2 domain as a potential inhibitor of the K15-PLCγ1 interaction. We first characterized the interaction between K15P and the isolated PLCγ2 cSH2 domain in more detail.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting the Recruitment of PLCγ1 to Kaposi’s Sarcoma Herpesvirus K15 Protein Reduces the Invasiveness and Angiogenesis of Infected Endothelial Cells

et al. 2015

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Kaposi’s sarcoma (KS), caused by Kaposi’s sarcoma herpesvirus (KSHV), is a highly vascularised tumour of endothelial origin. KSHV infected endothelial cells show increased invasiveness and angiogenesis. Here, we report that the KSHV K15 protein, which we showed previously to contribute to KSHV-induced angiogenesis, is also involved in KSHV-mediated invasiveness in a PLCγ1-dependent manner. We identified βPIX, GIT1 and cdc42, downstream effectors of PLCγ1 in cell migration, as K15 interacting partners and as contributors to KSHV-triggered invasiveness. We mapped the interaction between PLCγ1, PLCγ2 and their individual domains with two K15 alleles, P and M. We found that the PLCγ2 cSH2 domain, by binding to K15P, can be used as dominant negative inhibitor of the K15P-PLCγ1 interaction, K15P-dependent PLCγ1 phosphorylation, NFAT-dependent promoter activation and the increased invasiveness and angiogenic properties of KSHV infected endothelial cells. We increased the binding of the PLCγ2 cSH2 domain for K15P by substituting two amino acids, thereby creating an improved dominant negative inhibitor of the K15P-dependent PLCγ1 activation. Taken together, these results demonstrate a necessary role of K15 in the increased invasiveness and angiogenesis of KSHV infected endothelial cells and suggest the K15-PLCγ1 interaction as a possible new target for inhibiting the angiogenic and invasive properties of KSHV.

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“…We have reported that ablation of PLCγ2 results in a blockade of osteoclastogenesis owing to defective NFATc1 induction (11,22). PLCγ2-deficient mice are osteopetrotic and are also protected from inflammatory osteolysis (23,24).…”

Section: Resultsmentioning

confidence: 99%

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

Decker

Yang

Rimer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca 2+ ) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2 −/− mice, Tmem178 −/− mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca 2+ fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14 + monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.

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Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Cited by 9 publications

References 22 publications

Research update for articles published in EJCI in 2012

Research update for articles published in EJCI in 2012

Inhibiting the Recruitment of PLCγ1 to Kaposi’s Sarcoma Herpesvirus K15 Protein Reduces the Invasiveness and Angiogenesis of Infected Endothelial Cells

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

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