Mechanism of Stimulation of Osteoclastic Bone Resorption through Gas6/Tyro 3, a Receptor Tyrosine Kinase Signaling, in Mouse Osteoclasts

Katagiri, Mika; Hakeda, Yoshiyuki; Chikazu, Daichi; Ogasawara, Toru; Takato, Tsuyoshi; Kumegawa, Masayoshi; Nakamura, Kozo; Kawaguchi, Hiroshi

doi:10.1074/jbc.m007393200

Cited by 70 publications

(74 citation statements)

References 41 publications

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“…S6 E-G). Whereas the lack of alveolar bone loss in aged Gas6 −/− mice does not reflect the immunological and microbial status of their gingiva, it is in agreement with previous studies reporting that GAS6 is crucial for the resorption function of mature osteoclasts (22,23). Therefore, although Gas6 −/− mice should have an increased periodontal bone loss based on their periodontal immunological and microbial dysbiosis, the lack of Gas6 that prevents osteoclast function, ultimately, protects these mice from alveolar bone loss.…”

Section: Expression Of Gas6 In Epithelial Cells Rather Than Hematopoisupporting

confidence: 81%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

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

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The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6−/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.

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Section: Expression Of Gas6 In Epithelial Cells Rather Than Hematopoisupporting

confidence: 81%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

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

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“…TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 . In many of these instances, the primary downstream TAM signalling pathway appears to be the phosphoinositide 3-kinase-AKT pathway 95,97,99,102,103 , rather than the Janus kinase-STAT (signal transducer and activator of transcription) pathway that is highlighted in this Review.…”

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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“…However, the existence of a potential N-glycosylation site at position Asn 23 questions the involvement of Tyro3 in cell adhesion. Remarkably, this site is located at the center of the interface and is also present in Mer.…”

Section: Fig 1 Ligand Binding and Mutational Analysis Of Tyro3-d1d2mentioning

confidence: 99%

“…Gas6, a vitamin K-dependent protein encoded by growth arrest-specific gene 6 (17), binds to Axl, Tyro3, and Mer with nanomolar affinities (0.4, 2.9, and 29 nM, respectively) (18). The interaction between Axl and Gas6 has been implicated in cell adhesion processes (19,20), prevention of apoptosis (21), and cell proliferation (22), whereas Tyro3-Gas6 signaling was reported to stimulate osteoclastic bone resorption (23). In fibroblasts, high expression of Tyro3 or Axl has been found to cause transformation even in the absence of the ligand (9,24).…”

mentioning

confidence: 99%

Ligand Recognition and Homophilic Interactions in Tyro3

Heiring

Dahlbäck

Muller

2004

Journal of Biological Chemistry

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The receptor Tyro3 together with Axl and Mer form the Axl/Tyro3 family of receptor tyrosine kinases. Members of this family play essential roles in spermatogenesis, immunoregulation, and phagocytosis. Gas6, the product of growth arrest-specific gene, activates the kinase activity of all three receptors. Here, we report the first biochemical and structural characterization of a member of this family, namely of a fragment spanning the two N-terminal Ig domains of the extracellular part of human Tyro3. Its ligand binding specificity profile is identical to the activation profile of the native receptor. The 1.95-Å crystal structure suggests a common ligandbinding site in this receptor family located at the interface of the Ig domains and unusually rich in cis-prolines. Furthermore, both in the crystal and in solution we observed the ligand-independent dimerization of the receptor fragment. This homophilic interaction emphasizes previous functional reports, which hinted that in addition to signal transduction, members of this family of receptors might participate in cell adhesion.

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Mechanism of Stimulation of Osteoclastic Bone Resorption through Gas6/Tyro 3, a Receptor Tyrosine Kinase Signaling, in Mouse Osteoclasts

Cited by 70 publications

References 41 publications

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Immunobiology of the TAM receptors

Ligand Recognition and Homophilic Interactions in Tyro3

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