Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

Zawawi, Muhamad Syahrul Fitri; Dharmapatni, Anak; Cantley, Melissa; McHugh, Kevin P.; Haynes, David R.; Crotti, Tania

doi:10.1016/j.bbrc.2012.09.077

Cited by 25 publications

(23 citation statements)

References 35 publications

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“…Several immunoreceptors that pair with either DAP12 or FcRγ have been identified as costimulatory molecules for RANKL and while they share the ability to stimulate osteoclastogenesis, their expression is differentially regulated and responsive to distinct stimuli (2, 12). Ligands identified for some of these receptors are also differentially regulated, though most stimulatory ligands in the bone microenvironment are not well understood.…”

Section: Costimulation By Itam-signaling Adaptor-associated Immunorecmentioning

confidence: 99%

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Humphrey

Nakamura

2015

Clinic Rev Allerg Immunol

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Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. RANKL (Receptor Activator for NFkB ligand or TNFSF25), a TNF (tumor necrosis factor) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by ITAM (immunoreceptor tyrosine-based activation motif)-signaling adaptors, DAP12 (DNAX associated protein 12kD size) and FcRγ (FcεR1 gamma chain). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain, and therefore must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including TREM-2 (Triggering Receptor Expressed on Myeloid Cells 2), MDL-1 (Myeloid Dap-12 associated Lectin) and Siglec-15 (Sialic acid-binding immunoglobulin-type lectin15), while FcRγ pairs with a different set of receptors including OSCAR (Osteoclast Specific Activating Receptor), PIR-A (Paired Immunoglobulin Receptor A), and Fc Receptors. The ligands for many of these receptor in the bone microenvironment remain unknown. Here we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis, However, co-stimulation and the effects of ITAM-signaling have turned out to be complex including paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and ITIM (immunoreceptor tyrosine-based inhibitory motif) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.

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Section: Costimulation By Itam-signaling Adaptor-associated Immunorecmentioning

confidence: 99%

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Humphrey

Nakamura

2015

Clinic Rev Allerg Immunol

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“…Moreover, it has been shown to suppress the formation of osteoclasts by blocking the NFATc1 induction caused by tumor necrosis factor receptor-associated factor 6 (TRAF6) (60). NFATc1 induction by calcineurin signaling also plays an important role in osteoclast formation (43). In this study, we have demonstrated that panobinostat disturbed osteoclast formation and suppressed PPP3CA.…”

Section: R E S E a R C H A R T I C L E B Cells Deficient In Blimp1 (Tmentioning

confidence: 49%

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

et al. 2016

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“…11R-VIVIT induced inhibition of NFAT action was observed in neurons and glial cells in Alzheimer's disease [65]. Moreover, according to the literature, 11R-VIVIT was found to efficiently block transcriptional activity of NFAT, manifested by an arrested NFAT translocation [66], decreased NFAT expression in osteoclast differentiation [67], and by alterations of the expression pattern of genes being under its control [68], [69].…”

Section: Discussionmentioning

confidence: 99%

Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

et al. 2014

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BackgroundPlasma membrane Ca2+-ATPases (PMCA) extrude Ca2+ ions out of the cell and contribute to generation of calcium oscillations. Calcium signaling is crucial for transcriptional regulation of dopamine secretion by neuroendocrine PC12 cells. Low resting [Ca2+]c in PC12 cells is maintained mainly by two Ca2+-ATPases, PMCA2 and PMCA3. Recently, we found that Ca2+ dependent phosphatase calcineurin was excessively activated under conditions of experimental downregulation of PMCA2 or PMCA3. Thus, the aim of this study was to explain if, via modulation of the Ca2+/calcineurin-dependent nuclear factor of activated T cells (NFAT) pathway, PMCA2 and PMCA3 affect intracellular signaling in pheochromocytoma/neuronal cells/PC12 cells. Secondly, we tested whether this might influence dopamine secretion by PC12 cells.ResultsPMCA2- and PMCA3-deficient cells displayed profound decrease in dopamine secretion accompanied by a permanent increase in [Ca2+]c. Reduction in secretion might result from changes in NFAT signaling, following altered PMCA pattern. Consequently, activation of NFAT1 and NFAT3 transcription factors was observed in PMCA2- or PMCA3-deficient cells. Furthermore, chromatin immunoprecipitation assay indicated that NFATs could be involved in repression of Vamp genes encoding vesicle associated membrane proteins (VAMP).ConclusionsPMCA2 and PMCA3 are crucial for dopamine secretion in PC12 cells. Reduction in PMCA2 or PMCA3 led to calcium-dependent activation of calcineurin/NFAT signaling and, in consequence, to repression of the Vamp gene and deterioration of the SNARE complex formation in PC12 cells.

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Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

Cited by 25 publications

References 35 publications

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

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