Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-κB Transcriptional Activation

Tibrewal, Nitu; Yu, Wu; D’Mello, Veera; Akakura, Reiko; George, Thaddeus C.; Varnum, Brian; Birge, Raymond B.

doi:10.1074/jbc.m706906200

Cited by 125 publications

(130 citation statements)

References 48 publications

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“…Consistent with the observations in TAM-deficient mice that are outlined earlier, TLR activation of wild-type DCs has been found to be potently inhibited by prior incubation with either GAS6 or protein S 25,27 . TAM-mediated inhibition is seen irrespective of whether the TLR activated is TLR3, TLR4 or TLR9; and multiple points in TLR signal transduction cascades -including the activation of the p38 mitogen-activated protein kinase (MAPK), extracellular-signal-regulated kinase 1 (ERK1)/ERK2, nuclear factor-κB (NF-κB), tumournecrosis factor (TNF)-receptor-associated factor 3 (TRAF3) and TRAF6 -are inhibited.…”

Section: Tam Inhibition Of Inflammationsupporting

confidence: 86%

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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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Section: Tam Inhibition Of Inflammationsupporting

confidence: 86%

“…Similarly, it will be important to assess downstream TAM signalling pathways that mediate phagocytosis 62 versus those that are required for immunosuppression 25,27,56 . A recent report suggests that these pathways may be dissociable 27 .…”

Section: Box 2 | Primordial Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…BAI1 thus appears to activate a pathway corresponding to the CED-2/CED-5/CED-12-CED-10 axis in C. elegans. On the other hand, avb5 integrin (37) and Mer receptor tyrosine kinase (38), which indirectly recognize PS with the aid of the bridging molecules milk fat globule EGF factor 8 (39) and Gas6 (40), respectively, seem to prefer the pathway CED-2/CED-5/ CED-12-CED-10. These findings suggest that signalling pathways are defined not by the phagocytosis marker or eat-me signal, PS in this case, but by the structural nature of the phagocytosis receptor; that is, which adaptor GULP (CED-6) or CrkII (CED-2) the receptors may bind to.…”

Section: Resultsmentioning

confidence: 99%

Signalling Pathway Involving GULP, MAPK and Rac1 for SR-BI-Induced Phagocytosis of Apoptotic Cells

Osada

Sunatani

Kim

et al. 2009

Journal of Biochemistry

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Class B scavenger receptor type I (SR-BI) is a phosphatidylserine (PS)-recognizing receptor of testicular Sertoli cells responsible for the phagocytosis of spermatogenic cells undergoing apoptosis. Here, we determined signal mediators that compose a signalling pathway for SR-BI-induced phagocytosis. Results of a yeast twohybrid analysis and a cell-free binding assay indicated that SR-BI binds to engulfment adapter protein (GULP) using the C-terminal intracellular domain. A co-immunoprecipitation analysis showed the existence of a complex of GULP and SR-BI in cells prior to the activation of SR-BI by PS. A reduction of GULP expression in phagocytes decreased the SR-BI-mediated phagocytosis of apoptotic cells. Administration to phagocytes of PS-containing liposomes increased the levels of the GTP-bound form of Rac1 and the phosphorylated forms of mitogen-activated protein kinases (MAPK) p38 and extracellular signal-related kinase 1 and 2. Finally, lowering the expression of GULP abrogated MAPK phosphorylation, and the presence of MAPK inhibitors reduced the level of GTP-bound Rac1 in PS-activated phagocytes. These results collectively suggested the following signalling pathway for the SR-BI-induced phagocytosis: (i) PS-recognizing SR-BI activates associated GULP; (ii) activated GULP induces MAPK phosphorylation; (iii) activated MAPK increases GTP-bound Rac1; and (iv) activated Rac1 induces a rearrangement of the actin cytoskeleton.

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“…24 A dysregulation in macrophage efferocytosis may lead to autoimmunity and persistent inflammatory diseases. 25 Circulating blood monocytes were believed to be the exclusive precursors of tissue macrophages. 26 Monocytes derived from the bone marrow differentiate to macrophages in the intestine and the dermis during acute infection and inflammation.…”

Section: Macrophagesmentioning

confidence: 99%

Monocyte and Macrophage Plasticity in Tissue Repair and Regeneration

Das

Sinha

Datta

et al. 2015

The American Journal of Pathology

589

488

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Heterogeneity and high versatility are the characteristic features of the cells of monocyte-macrophage lineage. The mononuclear phagocyte system, derived from the bone marrow progenitor cells, is primarily composed of monocytes, macrophages, and dendritic cells. In regenerative tissues, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable. Macrophages are highly plastic cells. On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory type I macrophage (M1) or anti-inflammatory or proreparative type II macrophage (M2) phenotypes and transdifferentiate into other cell types. Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs. (Am J Pathol 2015, 185: 2596e2606; http://dx

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Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-κB Transcriptional Activation

Cited by 125 publications

References 48 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Signalling Pathway Involving GULP, MAPK and Rac1 for SR-BI-Induced Phagocytosis of Apoptotic Cells

Monocyte and Macrophage Plasticity in Tissue Repair and Regeneration

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