Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells

Anderson, Howard A.; Maylock, Caroline A.; Williams, Joy; Paweletz, Cloud P.; Shu, Hongjun; Shacter, Emily

doi:10.1038/ni871

Cited by 364 publications

(306 citation statements)

References 41 publications

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“…(Gla-domaincontaining proteins are prominent components of the blood coagulation cascade.) These Gla domains bind the phospholipid phosphatidylserine 13 , and this is an important feature of the in vivo function of GAS6 and protein S [14][15][16][17] . The Gla domain is followed by four epidermal growth factor (EGF)-like modules, and then by two tandem laminin G domains that are related to those of the sex hormone binding globulin (SHBG) (FIG.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

“…This defect is specific to the phagocytosis and clearance of apoptotic cells, and does not reflect diminished general phagocytic activity, as assayed by the uptake of labelled bacteria, yeast or latex spheres 42 . Particularly intriguing, with regard to the action of TAM receptors in macrophages, is the demonstration that the longrecognized ability of serum to stimulate cultured human macrophages to phagocytose apoptotic cells is due to the presence of protein S, and more specifically to its ability to bind phosphatidylserine 17 . An interaction between TAM and cytokine receptors during homeostatic phagocytosis has not been clearly demonstrated.…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

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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 Receptors and Ligandsmentioning

confidence: 99%

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…A sophisticated network of "eat-me" signals, phagocytic receptors, and bridging proteins orchestrates apoptotic cell clearance (1). Among the latter, serum proteins, including complement components and protein S, have been reported to play a role (3)(4)(5).…”

Section: E Limination Of Apoptotic Cells By Professional Phagocytes Ismentioning

confidence: 99%

“…Several serum proteins, including complement proteins and protein S, have been described to play a role in apoptotic cell clearance (3)(4)(5)13). We examined in depth the influence of human serum on apoptotic cell engulfment as measured by a flow cytometric phagocytosis assay (Supplemental Fig.…”

Section: Addition Of Human Serum Augments the Engulfment Of Apoptoticmentioning

confidence: 99%

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Rosenwald

Koppe

Keppeler

et al. 2012

The Journal of Immunology

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The elimination of apoptotic cells, called efferocytosis, is fundamentally important for tissue homeostasis and prevents the onset of inflammation and autoimmunity. Serum proteins are known to assist in this complex process. In the current study, we performed a multistep chromatographic fractionation of human serum and identified plasminogen, a protein involved in fibrinolysis, wound healing, and tissue remodeling, as a novel serum-derived factor promoting apoptotic cell removal. Even at levels significantly lower than its serum concentration, purified plasminogen strongly enhanced apoptotic prey cell internalization by macrophages. Plasminogen acted mainly on prey cells, whereas on macrophages no enhancement of the engulfment process was observed. We further demonstrate that the efferocytosis-promoting activity essentially required the proteolytic activation of plasminogen and was completely abrogated by the urokinase plasminogen activator inhibitor-1 and serine protease inhibitor aprotinin. Thus, our study assigns a new function to plasminogen and plasmin in apoptotic cell clearance.

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“…Cela favoriserait l'interaction entre la cellule apoptotique et le phagocyte [29] (Figure 3). Par ailleurs, le fractionnement du sérum a révélé que la protéine S est le principal facteur sérique capable de lier les phosphatidylsérines et de stimuler la phagocytose des cellules lymphoïdes en apoptose par les macrophages [30]. À ce titre, les protéines S et Gas6 se comportent comme de vraies jumelles.…”

Section: Système Visuelunclassified