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Heinz Furthmayr - One of the best experts on this subject based on the ideXlab platform.
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Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with Moesin and ezrin in myeloid cells
Blood, 2000Co-Authors: José Luis Alonso-lebrero, Karen R. Snapp, Geoffrey S. Kansas, Olga Barreiro, Juan M. Serrador, Carmen Domı́nguez-jiménez, Alfonso Luque, Miguel A. Pozo, Reinhard Schwartz-albiez, Heinz FurthmayrAbstract:In response to the chemoattractants interleukin 8, C5a, N -formyl-methionyl-leucyl-phenylalanine, and interleukin 15, adhesion molecules P-selectin glycoprotein ligand 1 (PSGL-1), intercellular adhesion molecule 3 (ICAM-3), CD43, and CD44 are redistributed to a newly formed uropod in human neutrophils. The adhesion molecules PSGL-1 and ICAM-3 were found to colocalize with the cytoskeletal protein Moesin in the uropod of stimulated neutrophils. Interaction of PSGL-1 with Moesin was shown in HL-60 cell lysates by isolating a complex with glutathione S-transferase fusions of the cytoplasmic domain of PSGL-1. Bands of 78- and 81-kd were identified as Moesin and ezrin by Western blot analysis. ICAM-3 and Moesin also coeluted from neutrophil lysates with an anti-ICAM-3 immunoaffinity assay. Direct interaction of the cytoplasmic domains of ICAM-3 and PSGL-1 with the amino-terminal domain of recombinant Moesin was demonstrated by protein-protein binding assays. These results suggest that the redistribution of PSGL-1 and its association with intracellular molecules, including the ezrin-radixin-Moesin actin-binding proteins, regulate functions mediated by PSGL-1 in leukocytes stimulated by chemoattractants.
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Regulation of F-Actin Binding to Platelet Moesin In Vitro by Both Phosphorylation of Threonine 558 and Polyphosphatidylinositides
Molecular biology of the cell, 1999Co-Authors: Fumihiko Nakamura, Laiqiang Huang, Kersi Pestonjamasp, Elizabeth J. Luna, Heinz FurthmayrAbstract:Activation of human platelets with thrombin transiently increases phosphorylation at 558threonine of Moesin as determined with phosphorylation state-specific antibodies. This specific modification is completely inhibited by the kinase inhibitor staurosporine and maximally promoted by the phosphatase inhibitor calyculin A, making it possible to purify the two forms of Moesin to homogeneity. Blot overlay assays with F-actin probes labeled with either [32P]ATP or 125I show that only phosphorylated Moesin interacts with F-actin in total platelet lysates, in Moesin antibody immunoprecipitates, and when purified. In the absence of detergents, both forms of the isolated protein are aggregated. Phosphorylated, purified Moesin co-sediments with α- or β/γ-actin filaments in cationic, but not in anionic, nonionic, or amphoteric detergents. The interaction affinity is high (Kd, ∼1.5 nM), and the maximal Moesin:actin stoichiometry is 1:1. This interaction is also observed in platelets extracted with cationic but not with nonionic detergents. In 0.1% Triton X-100, F-actin interacts with phosphorylated Moesin only in the presence of polyphosphatidylinositides. Thus, both polyphosphatidylinositides and phosphorylation can activate Moesin’s high-affinity F-actin binding site in vitro. Dual regulation by both mechanisms may be important for proper cellular control of Moesin-mediated linkages between the actin cytoskeleton and the plasma membrane.
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Moesin expression is associated with the estrogen receptor–negative breast cancer phenotype
Surgery, 1998Co-Authors: Charles Carmeci, Heinz Furthmayr, Devon A. Thompson, Wayne Kuang, Nina Lightdale, Ronald J. WeigelAbstract:Abstract Background: Estrogen receptor (ER)–positive breast carcinomas possess a less aggressive phenotype than ER-negative breast carcinomas. We hypothesize that a set of genes exists that is expressed only in ER-negative breast carcinomas, which account for the more malignant phenotypic characteristics of these tumors. Methods: We have used a new technique of polymerase chain reaction select suppression subtractive hybridization to identify genes that are expressed only in ER-negative carcinomas. Results: Seventy-one cDNA clones generated by suppression subtractive hybridization were screened by Northern blot analysis with RNA from ER-positive MCF7 and ER-negative MDA-MB-231 breast carcinoma cell lines. Fifteen clones were differentially expressed in MDA-MB-231 cells. Five of these 15 clones were consistently found to be associated with the ER-negative phenotype in a panel of eight breast carcinoma cell lines. Sequence analysis demonstrated that three of these clones were derived from vimentin and two clones from Moesin. Western blot analysis with antihuman Moesin antibody confirmed that Moesin protein was overexpressed in ER-negative breast carcinoma cell lines but absent from ER-positive breast carcinomas. Moesin mRNA was examined in a panel of 29 primary breast carcinomas with semiquantitative reverse transcriptase–polymerase chain reaction. Moesin expression was found to be decreased significantly in ER-positive compared with ER-negative tumors ( P Conclusions: Vimentin and Moesin are differentially expressed in association with the ER-negative breast cancer phenotype. Moesin is a membrane/actin filament protein involved in dynamic restructuring of the cell surface and filopodia, a cell structure needed for cell adhesion and motility. Moesin may play a role in the invasiveness and pattern of metastasis characteristic of ER-negative breast cancers. (Surgery 1998;124:211-17.)
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Phosphorylation of 558T of Moesin detected by site-specific antibodies in RAW264.7 macrophages.
Biochemical and biophysical research communications, 1996Co-Authors: Fumihiko Nakamura, Manuel R. Amieva, Chisako Hirota, Yoshito Mizuno, Heinz FurthmayrAbstract:To determine, whether558Thr in the carboxyl-terminal domain of Moesin is phosphorylated in cells other than platelets, rabbit phosphorylation state-specific antibodies were made to the chemically phosphorylated synthetic hexapeptide KYKpTLR of the Moesin sequence, as well as to the unphosphorylated form. The affinity-purified antibody populations were specific for either the phosphorylated or the unmodified peptide conjugated to BSA. Site-specific phosphorylation of Moesin is detected in RAW macrophages by Western blot analysis, and immunofluorescence studies demonstrate that phosphorylated Moesin is localized in filopodial protrusions. After pretreatment with the phosphatase inhibitor calyculin A, a similar effect to that seen in platelets is found, namely a substantial increase in Moesin phosphorylation at558Thr and redistribution of phospho-Moesin together with F-actin into one or more ring-like structures in the cytoplasm, presumably due to binding of phosphorylated Moesin to F-actin.
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the cytoskeletal linking proteins Moesin and radixin are upregulated by platelet derived growth factor but not basic fibroblast growth factor in experimental mesangial proliferative glomerulonephritis
Journal of Clinical Investigation, 1996Co-Authors: Claudia Hugo, Heinz Furthmayr, Manuel R. Amieva, Raimund Pichler, Katherine L Gordon, Rodney A Schmidt, William G Couser, Richard J JohnsonAbstract:The expression of the two cytoskeletal linking proteins, Moesin and radixin, was examined in experimental mesangial proliferative nephritis in rats (anti-Thy1 model). Moesin and radixin mRNA and protein are constitutively expressed in all cell types of normal rat glomeruli, except podocytes. In the anti-Thy1 model the expression of Moesin and radixin was increased in infiltrating macrophages and in activated, alpha-smooth muscle actin-positive mesangial cells and was concentrated in the cellular extensions of mesangial cells in areas of glomerular remodelling. Studies using neutralizing antibodies demonstrated that the increase in Moesin and radixin expression by mesangial cells is mediated by PDGF, but not bFGF. The increase in these cytoskeletal proteins appears to be regulated primarily (radixin) or partially (Moesin) posttranscriptionally. The data suggest that PDGF mediated upregulation of the cytoskeletal proteins, Moesin and radixin, is important for cell migration and other changes that accompany the coordinated restoration of glomerular architecture after injury.
François Payre - One of the best experts on this subject based on the ideXlab platform.
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Molecular networks linked by Moesin drive remodeling of the cell cortex during mitosis
The Journal of cell biology, 2011Co-Authors: Chantal Roubinet, François Payre, Barbara Decelle, Gaëtan Chicanne, Jonas F. Dorn, Bernard Payrastre, Sébastien CarrénoAbstract:The cortical mechanisms that drive the series of mitotic cell shape transformations remain elusive. In this paper, we identify two novel networks that collectively control the dynamic reorganization of the mitotic cortex. We demonstrate that Moesin, an actin/membrane linker, integrates these two networks to synergize the cortical forces that drive mitotic cell shape transformations. We find that the Pp1-87B phosphatase restricts high Moesin activity to early mitosis and down-regulates Moesin at the polar cortex, after anaphase onset. Overactivation of Moesin at the polar cortex impairs cell elongation and thus cytokinesis, whereas a transient recruitment of Moesin is required to retract polar blebs that allow cortical relaxation and dissipation of intracellular pressure. This fine balance of Moesin activity is further adjusted by Skittles and Pten, two enzymes that locally produce phosphoinositol 4,5-bisphosphate and thereby, regulate Moesin cortical association. These complementary pathways provide a spatiotemporal framework to explain how the cell cortex is remodeled throughout cell division.
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Moesin and its activating kinase Slik are required for cortical stability and microtubule organization in mitotic cells
The Journal of cell biology, 2008Co-Authors: Sébastien Carréno, Ilektra Kouranti, Edith Szafer Glusman, Margaret T. Fuller, Arnaud Echard, François PayreAbstract:Cell division requires cell shape changes involving the localized reorganization of cortical actin, which must be tightly linked with chromosome segregation operated by the mitotic spindle. How this multistep process is coordinated remains poorly understood. In this study, we show that the actin/membrane linker Moesin, the single ERM (ezrin, radixin, and Moesin) protein in Drosophila melanogaster, is required to maintain cortical stability during mitosis. Mitosis onset is characterized by a burst of Moesin activation mediated by a Slik kinase–dependent phosphorylation. Activated Moesin homogenously localizes at the cortex in prometaphase and is progressively restricted at the equator in later stages. Lack of Moesin or inhibition of its activation destabilized the cortex throughout mitosis, resulting in severe cortical deformations and abnormal distribution of actomyosin regulators. Inhibiting Moesin activation also impaired microtubule organization and precluded stable positioning of the mitotic spindle. We propose that the spatiotemporal control of Moesin activation at the mitotic cortex provides localized cues to coordinate cortical contractility and microtubule interactions during cell division.
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Light-regulated interaction of DMoesin with TRP and TRPL channels is required for maintenance of photoreceptors.
Journal of Cell Biology, 2005Co-Authors: Irit Chorna-ornan, François Payre, Vered Tzarfaty, Galit Ankri-eliahoo, Tamar Joel-almagor, Nina E Meyer, Armin Huber, Baruch MinkeAbstract:Recent studies in Drosophila melanogaster retina indicate that absorption of light causes the translocation of signaling molecules and actin from the photoreceptor's signaling membrane to the cytosol, but the underlying mechanisms are not fully understood. As ezrin-radixin-Moesin (ERM) proteins are known to regulate actin-membrane interactions in a signal-dependent manner, we analyzed the role of DMoesin, the unique D. melanogaster ERM, in response to light. We report that the illumination of dark-raised flies triggers the dissociation of DMoesin from the light-sensitive transient receptor potential (TRP) and TRP-like channels, followed by the migration of DMoesin from the membrane to the cytoplasm. Furthermore, we show that light-activated migration of DMoesin results from the dephosphorylation of a conserved threonine in DMoesin. The expression of a DMoesin mutant form that impairs this phosphorylation inhibits DMoesin movement and leads to light-induced retinal degeneration. Thus, our data strongly suggest that the light- and phosphorylation-dependent dynamic association of DMoesin to membrane channels is involved in maintenance of the photoreceptor cells.
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DMoesin controls actin-based cell shape and polarity during Drosophila melanogaster oogenesis
Nature Cell Biology, 2002Co-Authors: Cédric Polesello, Isabelle Delon, Philippe Valenti, Pierre Ferrer, François PayreAbstract:Ezrin, Radixin and Moesin (ERM) proteins are thought to constitute a bridge between the actin cytoskeleton and the plasma membrane (PM). Here we report a genetic analysis of DMoesin , the sole member of the ERM family in Drosophila . We show that DMoesin is required during oogenesis for anchoring microfilaments to the oocyte cortex. Alteration of the actin cytoskeleton resulting from DMoesin mutations impairs the localization of maternal determinants, thus disrupting antero–posterior polarity. This study also demonstrates the requirement of DMoesin for the specific organization of cortical microfilaments in nurse cells and, consequently, mutations in DMoesin produce severe defects in cell shape.
Takako Hirata - One of the best experts on this subject based on the ideXlab platform.
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The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance
Journal of immunology (Baltimore Md. : 1950), 2017Co-Authors: Hiroki Satooka, Daisuke Nagakubo, Tomomi Sato, Takako HirataAbstract:The ezrin-radixin-Moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and Moesin. Mutations in the Moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and Moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging Moesin-deficient mice develop a systemic lupus erythematosus-like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger Moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8+CD44+CD122+Ly49+ regulatory T (CD8+ Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8+ Treg cells from Moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that Moesin plays a key role in IL-15-mediated signaling. These findings underscore the importance of Moesin in IL-15-dependent CD8+ Treg cell homeostasis and, thus, the control of self-tolerance.
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Moesin regulates neutrophil rolling velocity in vivo.
Cellular immunology, 2016Co-Authors: Masanori Matsumoto, Takako HirataAbstract:During inflammation, the selectin-induced slow rolling of neutrophils on venules cooperates with chemokine signaling to mediate neutrophil recruitment into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) and CD44 as E-selectin ligands that activate integrins to induce slow rolling. We show here that in TNF-α-treated cremaster muscle venules, slow leukocyte rolling was impaired in mice deficient in Moesin, a member of the ezrin-radixin-Moesin (ERM) family. Accordingly, neutrophil recruitment in a peritonitis model was decreased in Moesin-deficient mice when chemokine signaling was blocked with pertussis toxin. These results suggest that Moesin contributes to the slow rolling and subsequent recruitment of neutrophils during inflammation.
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Moesin Controls Clathrin-Mediated S1PR1 Internalization in T Cells
PloS one, 2013Co-Authors: Akira Nomachi, Takeshi Watanabe, Shuh Narumiya, Masanori Yoshinaga, Jaron Liu, Pakorn Kanchanawong, Kiyoshi Tohyama, Dean Thumkeo, Takako HirataAbstract:The lipid mediator sphingosine 1-phosphate (S1P) regulates a wide range of cellular activities, including vascular maturation, angiogenesis, and immune-cell trafficking. Among the five known receptors for S1P (S1PR1-S1PR5), S1PR1 is a critical regulator of lymphocyte trafficking: its signaling is required for lymphocyte egress from lymphoid organs, while its down-modulation by agonist-induced internalization is a prerequisite for lymphocyte entry into lymphoid organs from the bloodstream. Despite the importance of S1PR1 down-regulation in determining lymphocyte behavior, the molecular mechanism of its internalization in lymphocytes has not been defined. Here we show that agonist-induced S1PR1 internalization in T cells occurs via clathrin-mediated endocytosis and is regulated by Moesin, an ezrin-radixin-Moesin (ERM) family member. In S1P-stimulated T cells, S1PR1 relocalized within clathrin-coated vesicles (CCVs) and early endosomes, and S1PR1 internalization was blocked when clathrin was pharmacologically inhibited. Stimulating Moesin-deficient T cells with S1P failed to induce S1PR1 internalization and CCV formation. Furthermore, treating Moesin-deficient mice with FTY720, an S1P receptor agonist known to internalize S1PR1, caused delayed lymphopenia, and lymphocytes isolated from FTY720-treated Moesin-deficient mice still responded to S1P ex vivo in chemotaxis assays. These results reveal a novel role for Moesin in regulating clathrin-dependent S1PR1 internalization through CCV formation.
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Moesin-deficient mice reveal a non-redundant role for Moesin in lymphocyte homeostasis.
International immunology, 2012Co-Authors: Takako Hirata, Akira Nomachi, Kazuo Tohya, Masayuki Miyasaka, Sachiko Tsukita, Takeshi Watanabe, Shuh NarumiyaAbstract:Moesin is a member of the ezrin–radixin–Moesin (ERM) family of cytoskeletal proteins. These proteins organize membrane domains by interacting with plasma membrane proteins and the actin cytoskeleton. Because of their high sequence similarity, ERM proteins are usually thought to be functionally redundant. Lymphocytes express two ERM proteins, ezrin and Moesin. Whether each ERM plays a specialized role in lymphocytes, particularly in vivo, remains unknown. Here, we show that Moesin has a crucial, non-redundant role in lymphocyte homeostasis. Moesin-deficient mice exhibited decreases in both T and B cells in the peripheral blood and lymph nodes, but not in the spleen. This phenotype was recapitulated in bone marrow (BM) chimeras with a hematopoietic Moesin deficiency. Although the T and B cells apparently developed without major defects in the Moesin-deficient mice, T cell egress from the thymus and immature B cell egress from the BM were impaired. In the periphery, both T and B cells showed delayed egress from lymphoid organs. We showed that Moesin is the primary phosphorylated ERM subject to dynamic regulation during cell shape changes and migration. Our findings identify a previously unknown, non-redundant function of Moesin in lymphocyte homeostasis in regulating lymphocyte egress from lymphoid organs.
Francisco Sánchez-madrid - One of the best experts on this subject based on the ideXlab platform.
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A juxta-membrane amino acid sequence of P-selectin glycoprotein ligand-1 is involved in Moesin binding and ezrin/radixin/Moesin-directed targeting at the trailing edge of migrating lymphocytes.
European journal of immunology, 2002Co-Authors: Juan M. Serrador, José Luis Alonso-lebrero, Ana Urzainqui, J. Román Cabrero, María C. Montoya, Miguel Vicente-manzanares, María Yáñez-mó, Francisco Sánchez-madridAbstract:P-selectin glycoprotein ligand 1 (PSGL-1) is an adhesion receptor localized on the tips of microvilli that is involved in the rolling of neutrophils on activated endothelium. We found that PSGL-1 was concentrated at the uropod of chemokine-stimulated lymphoid cells. Dynamic fluorescence videomicroscopy analyses of migrating lymphocytes demonstrated that PSGL-1 and Moesin redistributed towards the cellular uropod at the trailing edge of these cells, where activated ezrin/radixin/Moesin (ERM) proteins were located. An eighteen amino acid sequence in the juxta-membrane region of the PSGL-1 cytoplasmic tail was found to be critical for uropod targeting and Moesin binding. Substitution of S336, S348, and the basic cluster R337K338 by alanines within this region significantly impaired both Moesin binding and PSGL-1 polarization. These results underline the role of Moesin in the subcellular redistribution of PSGL-1 in lymphoid cells and make evident the importance of specific serine residues within the cytoplasmic tail of PSGL-1 for this process.
Juan M. Serrador - One of the best experts on this subject based on the ideXlab platform.
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A juxta-membrane amino acid sequence of P-selectin glycoprotein ligand-1 is involved in Moesin binding and ezrin/radixin/Moesin-directed targeting at the trailing edge of migrating lymphocytes.
European journal of immunology, 2002Co-Authors: Juan M. Serrador, José Luis Alonso-lebrero, Ana Urzainqui, J. Román Cabrero, María C. Montoya, Miguel Vicente-manzanares, María Yáñez-mó, Francisco Sánchez-madridAbstract:P-selectin glycoprotein ligand 1 (PSGL-1) is an adhesion receptor localized on the tips of microvilli that is involved in the rolling of neutrophils on activated endothelium. We found that PSGL-1 was concentrated at the uropod of chemokine-stimulated lymphoid cells. Dynamic fluorescence videomicroscopy analyses of migrating lymphocytes demonstrated that PSGL-1 and Moesin redistributed towards the cellular uropod at the trailing edge of these cells, where activated ezrin/radixin/Moesin (ERM) proteins were located. An eighteen amino acid sequence in the juxta-membrane region of the PSGL-1 cytoplasmic tail was found to be critical for uropod targeting and Moesin binding. Substitution of S336, S348, and the basic cluster R337K338 by alanines within this region significantly impaired both Moesin binding and PSGL-1 polarization. These results underline the role of Moesin in the subcellular redistribution of PSGL-1 in lymphoid cells and make evident the importance of specific serine residues within the cytoplasmic tail of PSGL-1 for this process.
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Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with Moesin and ezrin in myeloid cells
Blood, 2000Co-Authors: José Luis Alonso-lebrero, Karen R. Snapp, Geoffrey S. Kansas, Olga Barreiro, Juan M. Serrador, Carmen Domı́nguez-jiménez, Alfonso Luque, Miguel A. Pozo, Reinhard Schwartz-albiez, Heinz FurthmayrAbstract:In response to the chemoattractants interleukin 8, C5a, N -formyl-methionyl-leucyl-phenylalanine, and interleukin 15, adhesion molecules P-selectin glycoprotein ligand 1 (PSGL-1), intercellular adhesion molecule 3 (ICAM-3), CD43, and CD44 are redistributed to a newly formed uropod in human neutrophils. The adhesion molecules PSGL-1 and ICAM-3 were found to colocalize with the cytoskeletal protein Moesin in the uropod of stimulated neutrophils. Interaction of PSGL-1 with Moesin was shown in HL-60 cell lysates by isolating a complex with glutathione S-transferase fusions of the cytoplasmic domain of PSGL-1. Bands of 78- and 81-kd were identified as Moesin and ezrin by Western blot analysis. ICAM-3 and Moesin also coeluted from neutrophil lysates with an anti-ICAM-3 immunoaffinity assay. Direct interaction of the cytoplasmic domains of ICAM-3 and PSGL-1 with the amino-terminal domain of recombinant Moesin was demonstrated by protein-protein binding assays. These results suggest that the redistribution of PSGL-1 and its association with intracellular molecules, including the ezrin-radixin-Moesin actin-binding proteins, regulate functions mediated by PSGL-1 in leukocytes stimulated by chemoattractants.