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      The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis

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          Abstract

          TIM4 is a receptor for phosphatidylserine that mediates engulfment of apoptotic cells. Remarkably, it does not require its cytosolic or transmembrane domains to mediate phagocytosis. TIM4 associates with integrins that serve as signal-transducing coreceptors.

          Abstract

          T-cell immunoglobulin mucin protein 4 (TIM4), a phosphatidylserine (PtdSer)-binding receptor, mediates the phagocytosis of apoptotic cells. How TIM4 exerts its function is unclear, and conflicting data have emerged. To define the mode of action of TIM4, we used two distinct but complementary approaches: 1) we compared bone marrow–derived macrophages from wild-type and TIM4 −/− mice, and 2) we heterologously expressed TIM4 in epithelioid AD293 cells, which rendered them competent for engulfment of PtdSer-bearing targets. Using these systems, we demonstrate that rather than serving merely as a tether, as proposed earlier by others, TIM4 is an active participant in the phagocytic process. Furthermore, we find that TIM4 operates independently of lactadherin, which had been proposed to act as a bridging molecule. Of interest, TIM4-driven phagocytosis depends on the activation of integrins and involves stimulation of Src-family kinases and focal adhesion kinase, as well as the localized accumulation of phosphatidylinositol 3,4,5-trisphosphate. These mediators promote recruitment of the nucleotide-exchange factor Vav3, which in turn activates small Rho-family GTPases. Gene silencing or ablation experiments demonstrated that RhoA, Rac1, and Rac2 act synergistically to drive the remodeling of actin that underlies phagocytosis. Single-particle detection experiments demonstrated that TIM4 and β1 integrins associate upon receptor clustering. These findings support a model in which TIM4 engages integrins as coreceptors to evoke the signal transduction needed to internalize PtdSer-bearing targets such as apoptotic cells.

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          Most cited references 31

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          The Monte Carlo method.

           N METROPOLIS,  S ULAM (1949)
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            The ins and outs of leukocyte integrin signaling.

            Integrins are the principal cell adhesion receptors that mediate leukocyte migration and activation in the immune system. These receptors signal bidirectionally through the plasma membrane in pathways referred to as inside-out and outside-in signaling. Each of these pathways is mediated by conformational changes in the integrin structure. Such changes allow high-affinity binding of the receptor with counter-adhesion molecules on the vascular endothelium or extracellular matrix and lead to association of the cytoplasmic tails of the integrins with intracellular signaling molecules. Leukocyte functional responses resulting from outside-in signaling include migration, proliferation, cytokine secretion, and degranulation. Here, we review the key signaling events that occur in the inside-out versus outside-in pathways, highlighting recent advances in our understanding of how integrins are activated by a variety of stimuli and how they mediate a diverse array of cellular responses.
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              Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis

              Neutrophils exposed to chemoattractants polarize and accumulate polymerized actin at the leading edge. In neutrophil-like HL-60 cells, this asymmetry depends on a positive feedback loop in which accumulation of a membrane lipid, phosphatidylinositol (PI) 3,4,5-trisphosphate (PI[3,4,5]P3), leads to activation of Rac and/or Cdc42, and vice versa. We now report that Rac and Cdc42 play distinct roles in regulating this asymmetry. In the absence of chemoattractant, expression of constitutively active Rac stimulates accumulation at the plasma membrane of actin polymers and of GFP-tagged fluorescent probes for PI(3,4,5)P3 (the PH domain of Akt) and activated Rac (the p21-binding domain of p21-activated kinase). Dominant negative Rac inhibits chemoattractant-stimulated accumulation of actin polymers and membrane translocation of both fluorescent probes and attainment of morphologic polarity. Expression of constitutively active Cdc42 or of two different protein inhibitors of Cdc42 fails to mimic effects of the Rac mutants on actin or PI(3,4,5)P3. Instead, Cdc42 inhibitors prevent cells from maintaining a persistent leading edge and frequently induce formation of multiple, short lived leading edges containing actin polymers, PI(3,4,5)P3, and activated Rac. We conclude that Rac plays a dominant role in the PI(3,4,5)P3-dependent positive feedback loop required for forming a leading edge, whereas location and stability of the leading edge are regulated by Cdc42.
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                Author and article information

                Contributors
                Role: Monitoring Editor
                Journal
                Mol Biol Cell
                Mol. Biol. Cell
                molbiolcell
                mbc
                Mol. Bio. Cell
                Molecular Biology of the Cell
                The American Society for Cell Biology
                1059-1524
                1939-4586
                01 May 2014
                : 25
                : 9
                : 1511-1522
                Affiliations
                aProgram in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
                bFaculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada
                cKeenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5C 1N8, Canada
                University of Geneva
                Author notes
                1Address correspondence to: Sergio Grinstein ( sergio.grinstein@ 123456sickkids.ca ).
                Article
                E13-04-0212
                10.1091/mbc.E13-04-0212
                4004599
                24623723
                © 2014 Flannagan, Canton, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).

                “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.

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                Molecular biology

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