The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity

Behrens, Edwards M.; Gadue, Paul; Gong, Shunyou; Garrett, Stacey; Stein, Paul L.; Cohen, Philip L.

doi:10.1002/eji.200324076

Cited by 106 publications

(101 citation statements)

References 16 publications

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“…The basic finding is that NK cells isolated from TAM-deficient mice have very poor cytotoxic activity. As for the TAM-deficient phenotypes outlined above, the impairment of killing activity increases as more TAM genes are inactivated, consistent with the fact that all three receptors are expressed by immature NK cells in the bone marrow 22,76 . The acquisition of expression of inhibiting and activating receptors by these immature cells is driven by the stromal cells of the bone marrow, and these cells have been found to express both GAS6 and protein S 22 (FIG.…”

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confidence: 61%

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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confidence: 61%

Immunobiology of the TAM receptors

2008

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“…Mer is known to be expressed by many hematopoietic cell lineages, including macrophages, dendritic cells, NK cells, and NKT cells (Behrens et al, 2003). We examined Mer expression by flow cytometry in these cell lineages and found no difference in Mer surface protein levels between the Mer Tg and wild type (data not shown).…”

Section: Insertion Of the Mer Transgene Results In Expression Of Funcmentioning

confidence: 90%

Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase

et al. 2006

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“…Thus, while CR3-ligated BMDCs cannot tolerize T cells in culture, the secondary response of the T cell population is not as high as would be expected from T cells initially stimulated by normal BMDCs. It is likely that the simultaneous activation of multiple apoptotic cell receptors such as CD36, or mer (47), is required to commit DCs to tolerance. This may be in part due to the fact that CR3 acts in an inflammatory manner when activated in nonapoptotic cell contexts such as when ligated by certain bacterial products (37).…”

Section: Discussionmentioning

confidence: 99%

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

Behrens

Sriram

Shivers

et al. 2007

The Journal of Immunology

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To activate T cells effectively, dendritic cells (DCs) must provide three separate signals, MHC-Ag, costimulatory molecules (such as CD80 and CD86), and proinflammatory cytokines (such as IL-12). These three signals are up-regulated in the presence of “danger signals” such as LPS or viral nucleic acids. Evidence suggests that DCs providing only the first two of these signals cannot successfully stimulate T cells. Apoptotic cells have been proposed to suppress DC immunogenicity through the ligation of apoptotic cell receptors. Complement receptor 3 (CR3) and CD36 have been suggested to be important in this process, although the mechanism by which this modulation occurs is still unclear. We demonstrate that ligation of CR3, but not CD36, directs DCs to increase surface MHC and costimulatory molecules, while suppressing inflammatory cytokine release. CR3 modulation of DCs does not require a type I IFN response, does not involve the specific regulation of the MyD88- or Toll/IL-1R domain-containing adaptor-inducing IFN-β-dependent TLR signaling pathways, and occurs even in the absence of danger signals. The functional outcome of this process is poor Ag-specific stimulation of CD4 and CD8 T cells by CR3-ligated DCs both in naive response as well as upon subsequent challenge with normal DCs. We propose that CR3 provides a “nondanger” signal that suppresses the stimulatory capacity of DCs.

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The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity

Cited by 106 publications

References 16 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

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