Genomes and Genes
Summary: Integrin alpha4beta1 is a FIBRONECTIN and VCAM-1 receptor present on LYMPHOCYTES; MONOCYTES; EOSINOPHILS; NK CELLS and thymocytes. It is involved in both cell-cell and cell- EXTRACELLULAR MATRIX adhesion and plays a role in INFLAMMATION, hematopoietic cell homing and immune function, and has been implicated in skeletal MYOGENESIS; NEURAL CREST migration and proliferation, lymphocyte maturation and morphogenesis of the PLACENTA and HEART.
- Lim C, Han J, Yousefi N, Ma Y, Amieux P, McKnight G, et al. Alpha4 integrins are type I cAMP-dependent protein kinase-anchoring proteins. Nat Cell Biol. 2007;9:415-21 pubmed
- Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436:266-71 pubmed..These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection. ..
- Binsky I, Lantner F, Grabovsky V, Harpaz N, Shvidel L, Berrebi A, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184:4761-9 pubmed publisher..These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival. ..
- Hyun Y, Chung H, McGrath J, Waugh R, Kim M. Activated integrin VLA-4 localizes to the lamellipodia and mediates T cell migration on VCAM-1. J Immunol. 2009;183:359-69 pubmed publisher..These data suggest that a subpopulation of activated VLA-4 is mainly localized to the leading edge of polarized human T cells and is critical for T cell migration on VCAM-1. ..
- Hyduk S, Chan J, Duffy S, Chen M, Peterson M, Waddell T, et al. Phospholipase C, calcium, and calmodulin are critical for alpha4beta1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood. 2007;109:176-84 pubmed..A critical role for PLC and calmodulin was also established for leukocyte arrest and adhesion strengthening. ..
- Verdone G, Doliana R, Corazza A, Colebrooke S, Spessotto P, Bot S, et al. The solution structure of EMILIN1 globular C1q domain reveals a disordered insertion necessary for interaction with the alpha4beta1 integrin. J Biol Chem. 2008;283:18947-56 pubmed publisher..Thus, EMILIN1 gC1q-alpha4beta1 represents a unique ligand/receptor system, with a requirement for a 3-fold arrangement of the interaction site. ..
- Chigaev A, Waller A, Zwartz G, Buranda T, Sklar L. Regulation of cell adhesion by affinity and conformational unbending of alpha4beta1 integrin. J Immunol. 2007;178:6828-39 pubmed
- Niino M, Bodner C, Simard M, Alatab S, Gano D, Kim H, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006;59:748-54 pubmed..Monitoring these parameters could be relevant to ongoing safety and efficacy considerations. ..
- Brachtl G, Sahakyan K, Denk U, Girbl T, Alinger B, Hofbauer S, et al. Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells. PLoS ONE. 2011;6:e23758 pubmed publisher..Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells. ..
- Woodside D, Kram R, Mitchell J, Belsom T, Billard M, McIntyre B, et al. Contrasting roles for domain 4 of VCAM-1 in the regulation of cell adhesion and soluble VCAM-1 binding to integrin alpha4beta1. J Immunol. 2006;176:5041-9 pubmedCell adhesion mediated by the interaction between integrin alpha4beta1 and VCAM-1 is important in normal physiologic processes and in inflammatory and autoimmune disease...
- Carrasco Y, Batista F. B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J. 2006;25:889-99 pubmed..These results show that the VLA-4/VCAM-1 interaction during membrane antigen recognition enhances B-cell activation and this function appears to be independent of its final peripheral localization at the IS. ..
- Dikeman D, Rivera Rosado L, Horn T, Alves C, Konstantopoulos K, Yang J. alpha4 beta1-Integrin regulates directionally persistent cell migration in response to shear flow stimulation. Am J Physiol Cell Physiol. 2008;295:C151-9 pubmed publisher..These findings provide a new insight into the mechanism by which integrins regulate directionally persistent cell migration. ..
- Muro F, Iimura S, Yoneda Y, Chiba J, Watanabe T, Setoguchi M, et al. Identification of 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist. Bioorg Med Chem. 2008;16:9991-10000 pubmed publisher..Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model. ..
- Humphries J, Humphries M. CD14 is a ligand for the integrin alpha4beta1. FEBS Lett. 2007;581:757-63 pubmedCell adhesion mediated by the integrin alpha4beta1 plays a key role in many biological processes reflecting both the number and functional significance of alpha4beta1 ligands...
- Ghandour H, Cullere X, Alvarez A, Luscinskas F, Mayadas T. Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion. Blood. 2007;110:3682-90 pubmed..Thus, PLC/CalDAG-GEFI regulation of Rap1 is selectively required for chemokine- and PMA-induced LFA-1 activation in human T cells, whereas alternate PLC- and PKC-dependent mechanisms are involved in the regulation of VLA-4. ..
- Mraz M, Zent C, Church A, Jelinek D, Wu X, Pospisilova S, et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin ?-4-?-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol. 2011;155:53-64 pubmed publisher..These pre-clinical findings suggest that the addition of stromal adhesion-disruptive drugs to rituximab-containing therapy could improve treatment efficacy. ..
- Sixt M, Bauer M, Lämmermann T, Fassler R. Beta1 integrins: zip codes and signaling relay for blood cells. Curr Opin Cell Biol. 2006;18:482-90 pubmed..Genetic mouse models where integrins are selectively deleted on blood cells have been used to investigate these functions and further studies will be invaluable to critically evaluate therapeutic trials. ..
- Redondo Muñoz J, Escobar Díaz E, Samaniego R, Terol M, Garcia Marco J, Garcia Pardo A. MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha4beta1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration. Blood. 2006;108:3143-51 pubmed..MMP-9 could therefore constitute a target for treatment of this malignancy. ..
- Peng L, Liu R, Marik J, Wang X, Takada Y, Lam K. Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging. Nat Chem Biol. 2006;2:381-9 pubmed..Thus, LLP2A provides an important tool for noninvasive monitoring of alpha4beta1 expression and activity during tumor progression, and it shows great potential as an imaging and therapeutic agent for alpha4beta1-positive tumors. ..
- Chigaev A, Wu Y, Williams D, Smagley Y, Sklar L. Discovery of very late antigen-4 (VLA-4, alpha4beta1 integrin) allosteric antagonists. J Biol Chem. 2011;286:5455-63 pubmed publisher..Because all the identified compounds are structurally related, previously used, or currently marketed drugs, this result opens a range of therapeutic possibilities for VLA-4-related pathologies...
- Garmy Susini B, Jin H, Zhu Y, Sung R, Hwang R, Varner J. Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest. 2005;115:1542-51 pubmed..Here we show that integrin alpha4beta1 (VLA-4) and VCAM-1 promote close intercellular adhesion between ECs and pericytes and that this interaction ..
- Schmid M, Avraamides C, Dippold H, Franco I, Foubert P, Ellies L, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3k?, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19:715-27 pubmed publisher..Pharmacological or genetic blockade of p110? suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology. ..
- Humphries J, Byron A, Bass M, Craig S, Pinney J, Knight D, et al. Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Sci Signal. 2009;2:ra51 pubmed publisher..This proteomics workflow now opens the way to further dissection and systems-level analyses of adhesion signaling. ..
- Rullo J, Becker H, Hyduk S, Wong J, Digby G, Arora P, et al. Actin polymerization stabilizes ?4?1 integrin anchors that mediate monocyte adhesion. J Cell Biol. 2012;197:115-29 pubmed publisher..These included activation of Rap1, phosphoinositide 3-kinase ? isoform, and Rac but not Cdc42. Thus, rapid signaling and structural adaptations enable leukocytes to stabilize adhesion and resist detachment forces. ..
- Hsia D, Lim S, Bernard Trifilo J, Mitra S, Tanaka S, den Hertog J, et al. Integrin alpha4beta1 promotes focal adhesion kinase-independent cell motility via alpha4 cytoplasmic domain-specific activation of c-Src. Mol Cell Biol. 2005;25:9700-12 pubmed
- Nguyen K, Sylvain N, Bunnell S. T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76. Immunity. 2008;28:810-21 pubmed publisher..These data suggest a widely applicable model of costimulation, in which integrins promote sustained signaling by attenuating cytoskeletal movements that drive the centralization and inactivation of SLP-76 microclusters. ..
- Eshghi S, Vogelezang M, Hynes R, Griffith L, Lodish H. Alpha4beta1 integrin and erythropoietin mediate temporally distinct steps in erythropoiesis: integrins in red cell development. J Cell Biol. 2007;177:871-80 pubmed
- Sedgwick J, Jansen K, Kennedy J, Kita H, Busse W. Effects of the very late adhesion molecule 4 antagonist WAY103 on human peripheral blood eosinophil vascular cell adhesion molecule 1-dependent functions. J Allergy Clin Immunol. 2005;116:812-9 pubmed
- Kenyon N, Liu R, O Roark E, Huang W, Peng L, Lam K. An alpha4beta1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice. Eur J Pharmacol. 2009;603:138-46 pubmed publisher..Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin, presumably by improving the circulating half-life of the drug. ..
- Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele J, Zwartkruis F. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol Cell Biol. 2006;26:643-53 pubmed..Although it is possible that the relatively mild phenotype is a consequence of functional complementation by the Rap1B gene, our genetic studies confirm a role for Rap1A in the regulation of integrins. ..
- Steinman L. A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol. 2009;9:440-7 pubmed publisher..This Review discusses how this molecular trio interacts to initiate relapses (in the case of osteopontin and alpha4beta1 integrin) and then to terminate them as remissions in multiple sclerosis (in the case of alphaB crystallin). ..
- Chigaev A, Waller A, Amit O, Sklar L. Galphas-coupled receptor signaling actively down-regulates alpha4beta1-integrin affinity: a possible mechanism for cell de-adhesion. BMC Immunol. 2008;9:26 pubmed publisher..This plays an essential role in the regulation of cell adhesion. We discuss several possible implications of this described phenomenon. ..
- Hyduk S, Rullo J, Cano A, Xiao H, Chen M, Moser M, et al. Talin-1 and kindlin-3 regulate alpha4beta1 integrin-mediated adhesion stabilization, but not G protein-coupled receptor-induced affinity upregulation. J Immunol. 2011;187:4360-8 pubmed publisher..Talin-1 contributed to ?(4)?(1)-dependent chemotaxis, suggesting that it participates in a later stage of the leukocyte adhesion cascade when the leukocyte cytoskeleton undergoes dramatic rearrangement...
- Garmy Susini B, Avraamides C, Schmid M, Foubert P, Ellies L, Barnes L, et al. Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res. 2010;70:3042-51 pubmed publisher..We show here that the fibronectin-binding integrin alpha4beta1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium...
- Parmo Cabañas M, García Bernal D, Garcia Verdugo R, Kremer L, Marquez G, Teixido J. Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1. J Leukoc Biol. 2007;82:380-91 pubmed
- Warnke C, Menge T, Hartung H, Racke M, Cravens P, Bennett J, et al. Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided?. Arch Neurol. 2010;67:923-30 pubmed publisher..In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment...
- Grazioli A, Alves C, Konstantopoulos K, Yang J. Defective blood vessel development and pericyte/pvSMC distribution in alpha 4 integrin-deficient mouse embryos. Dev Biol. 2006;293:165-77 pubmed
- Pirson L, Baron F, Meuris N, Giet O, Castermans E, Greimers R, et al. Despite inhibition of hematopoietic progenitor cell growth in vitro, the tyrosine kinase inhibitor imatinib does not impair engraftment of human CD133+ cells into NOD/SCIDbeta2mNull mice. Stem Cells. 2006;24:1814-21 pubmed..In summary, our results suggest that, despite inhibition of hematopoietic progenitor cell growth in vitro, imatinib does not interfere with hematopoietic stem cell engraftment. ..
- Zohren F, Toutzaris D, Klärner V, Hartung H, Kieseier B, Haas R. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood. 2008;111:3893-5 pubmed publisher..001), including pluripotent cells in colony-forming assays. This mobilizing ability of natalizumab might be useful for patients with poor response to granulocyte colony-stimulating factor (G-CSF)-based protocols. ..
- Bauer M, Brakebusch C, Coisne C, Sixt M, Wekerle H, Engelhardt B, et al. Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc Natl Acad Sci U S A. 2009;106:1920-5 pubmed publisher..Collectively, these results suggest that the primary action of natalizumab is interference with T cell extravasation via inhibition of alpha(4)beta(1) integrins. ..
- Ecoiffier T, El Annan J, Rashid S, Schaumberg D, Dana R. Modulation of integrin alpha4beta1 (VLA-4) in dry eye disease. Arch Ophthalmol. 2008;126:1695-9 pubmed publisher..To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti-VLA-4 sm) in a mouse model of dry eye disease...
- DiVietro J, Brown D, Sklar L, Larson R, Lawrence M. Immobilized stromal cell-derived factor-1alpha triggers rapid VLA-4 affinity increases to stabilize lymphocyte tethers on VCAM-1 and subsequently initiate firm adhesion. J Immunol. 2007;178:3903-11 pubmed..Chemokine activation of PBL firm adhesion on VCAM-1 depended on induction of high-affinity VLA-4 rather than recruitment of a pre-existing pool of high-affinity VLA-4 as previously thought. ..
- García Bernal D, Sotillo Mallo E, Nombela Arrieta C, Samaniego R, Fukui Y, Stein J, et al. DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin alpha4beta1. J Immunol. 2006;177:5215-25 pubmed
- Barthel S, Annis D, Mosher D, Johansson M. Differential engagement of modules 1 and 4 of vascular cell adhesion molecule-1 (CD106) by integrins alpha4beta1 (CD49d/29) and alphaMbeta2 (CD11b/18) of eosinophils. J Biol Chem. 2006;281:32175-87 pubmed..These results demonstrate that alphaMbeta2 modulatesalpha4beta1-mediated eosinophil adhesion to VCAM-1 under both static and flow conditions. ..
- Redondo Muñoz J, Ugarte Berzal E, Garcia Marco J, Del Cerro M, Van Den Steen P, Opdenakker G, et al. Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood. 2008;112:169-78 pubmed publisher..Thus, we have identified alpha4beta1 and CD44v as a novel proMMP-9 cell surface docking complex and show that cell-associated MMP-9 may regulate B-CLL cell migration and arrest. ..
- Noborio Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, et al. Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene. 2009;28:231-42 pubmed publisher..These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM. ..
- Chigaev A, Waller A, Amit O, Halip L, Bologa C, Sklar L. Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation. J Biol Chem. 2009;284:14337-46 pubmed publisher..Our data suggest that VLA-4 integrin hybrid domain movement does not depend on the affinity state of the ligand binding pocket. ..
- Klemke M, Weschenfelder T, Konstandin M, Samstag Y. High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J Cell Physiol. 2007;212:368-74 pubmed..Moreover, we demonstrate that function-blocking antibodies against the integrin alpha4beta1, as well as siRNA-mediated knock-down of the alpha4 subunit in these highly metastatic human melanoma cells ..
- Redondo Muñoz J, Ugarte Berzal E, Terol M, Van Den Steen P, Hernández Del Cerro M, Roderfeld M, et al. Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. Cancer Cell. 2010;17:160-72 pubmed publisher..Our results establish that MMP/receptor binding induces intracellular survival signals and highlight the role of (pro)MMP-9 in B-CLL pathogenesis. ..