Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Park, Eun Jeong; Mora, J. Rodrigo; Carman, Christopher V.; Chen, Jianfeng; Sasaki, Yoshiyuki; Cheng, George; Andrian, Ulrich H. von; Shimaoka, Motomu

doi:10.1172/jci31570

Cited by 66 publications

(66 citation statements)

References 54 publications

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“…In agreement with this hypothesis, our flow cytometric and biotinylation analyses showed that S3-5 mutant cells highly expressed the active form of ␣5␤1 on the cell surface. Similarly, Park et al previously reported that aberrant activation of integrin ␣4␤7 suppressed lymphocyte migration and underscored the importance of a proper balance in the adhesion and de-adhesion of integrin (34). The enhanced expression of active ␤1 on the cell surface might have been due to different trafficking events, since the internalization of the active form of ␣5␤1 but not the total version was significantly delayed in S3-5 cells compared with that in WT cells.…”

Section: Discussionmentioning

confidence: 75%

A Key Regulator of Cell Adhesion: Identification and Characterization of Important N-Glycosylation Sites on Integrin α5 for Cell Migration

Hang

Isaji

Hou

et al. 2017

Molecular and Cellular Biology

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The N-glycosylation of integrin ␣5␤1 is thought to control many fundamental aspects of cell behavior, including cell adhesion and migration. However, the mechanism of how N-glycans function remains largely obscure. Here, we used a loss-of-function approach. Wild-type (WT) integrin ␣5 and N-glycosylation mutant S3-5 (sites 3 to 5) integrin ␣5, which contains fewer N-glycans, were stably reconstituted in ␣5 knockout cancer cells. We found that the migration ability of S3-5 cells was decreased in comparison with that of the WT. Interestingly, the levels of phosphorylated focal adhesion kinase and actin stress fiber formation were greatly enhanced in the S3-5 mutant. In a mechanistic manner, the internalization of active but not total integrin ␣5␤1 was inhibited in S3-5 cells, which is a process that is related to the enhanced expression of active integrin ␣5␤1 on the cell surface. Importantly, restoration of N-glycosylation on the ␤-propeller domain of ␣5 reinstated the cell migration ability, active ␣5␤1 expression, and internalization. Moreover, these N-glycans are critical for ␣5-syndecan-4 complex formation. These findings indicate that N-glycosylation on the ␤-propeller domain functions as a molecular switch to control the dynamics of ␣5␤1 on the cell surface that in turn is required for optimum adhesion for cell migration.KEYWORDS N-glycan, activation, complex formation, internalization C ell migration is essential not only for normal physiological processes such as embryonic development and wound healing but also for pathological changes such as inflammatory disease and cancer (1). Integrin, the ␣␤ heterodimeric transmembrane receptor, plays a central role in cell migration by connecting an extracellular matrix (ECM) to the cytoskeleton as well as functioning as a bidirectional signaling molecule that transmits information across the cell membrane (2). Due to its importance, integrin has been highly implicated in the development of tumor malignancy. Therefore, a detailed molecular understanding of the mechanisms involved in integrinmediated tumor cell migration is very important for our ability to intervene in the procession of cancer.In mammals, different ␣ and ␤ subunit combinations make up a total of 24 integrins. Integrins are found in either active or inactive conformations with respect to their high or low affinity for their ECM ligands (3), and an allosteric change that favors high affinity can be induced by either cytoplasmic events ("inside-out" activation) or extracellular factors ("outside-in" activation) (4), which triggers integrin clustering, cytoskeletal remodeling, and the assembly of cell adhesion complexes, including focal adhesion (FA) and fibrillary adhesion (5). Indeed, cell migration is a highly dynamic process that

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Section: Discussionmentioning

confidence: 75%

A Key Regulator of Cell Adhesion: Identification and Characterization of Important N-Glycosylation Sites on Integrin α5 for Cell Migration

Hang

Isaji

Hou

et al. 2017

Molecular and Cellular Biology

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“…Integrins must be regulated to be activated and deactivated quickly in mammalian cells, even within seconds. It has been shown that detachment of integrin from ligands in the trailing edge is critical for integrin functions (46), and mutations that constitutively active integrins result in malfunctions (47)(48)(49)(50). Therefore, it is unlikely that integrin TM domains form more stable homomeric association during inside-out signaling.…”

Section: Discussionmentioning

confidence: 99%

Tests of Integrin Transmembrane Domain Homo-oligomerization during Integrin Ligand Binding and Signaling

Wang

Zhu

Springer

et al. 2011

Journal of Biological Chemistry

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Integrin transmembrane (TM) and/or cytoplasmic domains play a critical role in integrin bidirectional signaling. Although it has been shown that TM and/or cytoplasmic ␣ and ␤ domains associate in the resting state and separation of these domains is required for both inside-out and outside-in signaling, the role of TM homomeric association remains elusive. Formation of TM homo-oligomers was observed in micelles and bacterial membranes previously, and it has been proposed that homomeric association is important for integrin activation and clustering. This study addresses whether integrin TM domains form homo-oligomers in mammalian cell membranes using cysteine scanning mutagenesis. Our results show that TM homomeric interaction does not occur before or after soluble ligand binding or during inside-out activation. In addition, even though the cysteine mutants and the heterodimeric disulfide-bounded mutant could form clusters after adhering to immobilized ligand, the integrin TM domains do not form homo-oligomers, suggesting that integrin TM homomeric association is not critical for integrin clustering or outside-in signaling. Therefore, integrin TM homo-oligomerization is not required for integrin activation, ligand binding, or signaling.Integrins are cell adhesion molecules that are essential for many biological functions such as cell migration, survival, and differentiation. These functions are accomplished by integrin bidirectional signaling across the cell membrane. Inside-out activation occurs when specific intracellular molecules such as talin and kindlin bind to the integrin cytoplasmic domain, leading to integrin conformational change and therefore high affinity for extracellular ligands. Then, binding of multimeric extracellular ligands results in outside-in signaling that is critical for many cellular processes. It has been shown that integrin bidirectional signal transduction requires integrin structural change and lateral distribution (clustering) (1, 2).Integrins are type I transmembrane (TM) 2 proteins consisting of two noncovalently associated ␣ and ␤ subunits, each with a large extracellular domain, a single-span TM domain, and a short cytoplasmic domain. Recent structural studies have greatly advanced our understanding of integrin conformational change during inside-out activation (3-9). Even though relatively short, the integrin TM/cytoplasmic domains play a crucial role in this process. It has been shown that the association of ␣ and ␤ subunit TM/cytoplasmic domains is critical for stabilizing integrins in the resting state (10 -16). When induced by binding of the ␤ subunit cytoplasmic domain through talin or other intracellular molecules, the TM/ cytoplasmic domains separate (17, 18), driving integrin extension and shifting the ligand binding ␣/␤ headpiece to an open, high affinity conformation (7,19). Recently, the structure of the TM/cytoplasmic domains in the resting state was proposed based on Rosetta computational modeling and experimental data using intact integrins on mammalian cell surfa...

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“…The importance of the a 4 b 7 integrin was further evaluated through the manipulation of an integrin regulatory domain (adjacent to metal iondependent adhesion site [ADMIDAS]), a domain that normally serves to raise the activation threshold of a 4 b 7 and stabilize it in the nonadhesive state [Park et al 2007]. Lymphocytes from mice harboring a disrupted ADMIDAS expressed an a 4 b 7 integrin that persistently adhered to MAdCAM-1 and also exhibited improper de-adhesion.…”

Section: Approaches To Targeting Adhesion Molecules and Their Associamentioning

confidence: 99%

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Ghosh

Panaccione

2010

Therap Adv Gastroenterol

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Although biologic agents directed against tumor necrosis factor alpha (TNFa) continue to be an effective therapeutic strategy for patients with inflammatory bowel disease (IBD), approximately 30% of patients with Crohn's disease (CD) who are refractory to standard treatment do not respond to induction therapy with TNFa inhibitors and, of those who initially respond, 50% or more cease to respond within a year. Moreover, their use can be associated with significant safety issues. Clearly, there is a need to target alternative pathways involved in the inflammatory process. IBD is driven by the trafficking of lymphocytes from the circulation into the gut tissue that is mediated by adhesive interactions between the lymphocytes and endothelial cells. The adhesion molecules involved represent attractive targets for the development of new therapeutics which should aid in the resolution of existing inflammation, prevent recurrence of inflammation, and may potentially lead to long-term control of disease. In this article we review current opportunities and challenges facing anti-adhesion therapy in IBD, and discusses recent clinical development efforts that have focused on having an impact on two particular adhesive interactions: a 4 -integrin/MAdCAM-1 and b 2 -integrin/ICAM-1. Of particular interest is natalizumab, a humanized monoclonal antibody against human a 4 integrin that is approved for the treatment of patients with moderately-to-severely active CD and evidence of active inflammation. This agent represents an efficacious therapeutic option for patients who do not respond to, or have failed, a TNF-a inhibitor.

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Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Cited by 66 publications

References 54 publications

A Key Regulator of Cell Adhesion: Identification and Characterization of Important N-Glycosylation Sites on Integrin α5 for Cell Migration

A Key Regulator of Cell Adhesion: Identification and Characterization of Important N-Glycosylation Sites on Integrin α5 for Cell Migration

Tests of Integrin Transmembrane Domain Homo-oligomerization during Integrin Ligand Binding and Signaling

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

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