Activation and suppression of hematopoietic integrins in hemostasis and immunity

Nolte, Martijn A.; Margadant, Coert

doi:10.1182/blood.2019003336

Cited by 23 publications

(13 citation statements)

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“…Integrins are essential for hemostasis and immunity, because they regulate platelet aggregation, leukocyte adhesion and migration, and transforming growth factor-β activation [ 34 , 35 ]. In addition, it is becoming clear that integrins also control vesicular trafficking in platelets and leukocytes at several levels.…”

Section: Integrin Adhesion Complexes Regulate Platelet and Leukocyte mentioning

confidence: 99%

“…Integrin cytoplasmic tails can induce profound differences in the behavior of distinct integrins, even when they bind the same ligand [ 64 ], which is most likely due to differences in the relative affinities for specific proteins. The cytotail of αvβ5 contains an insert of eight amino acids, as compared with integrin β1 or β3 tails [ 34 ], and may have an exceptionally high affinity for clathrin adaptors. Consistent with this idea is the observation that swapping the β5 tail with that of β1 or β3 induces a redistribution to FAs [ 59 ].…”

Section: Integrin Crosstalk With the Endocytic Machinery Regulates Admentioning

confidence: 99%

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Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Nolte

Hoen

Margadant³

2021

Trends in Biochemical Sciences

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Integrins are transmembrane receptors that transduce biochemical and mechanical signals across the plasma membrane and promote cell adhesion and migration. In addition, integrin adhesion complexes are functionally and structurally linked to components of the intracellular trafficking machinery and accumulating data now reveal that they are key regulators of endocytosis and exocytosis in a variety of cell types. Here, we highlight recent insights into integrin control of intracellular trafficking in processes such as degranulation, mechanotransduction, cell–cell communication, antibody production, virus entry, Toll-like receptor signaling, autophagy, and phagocytosis, as well as the release and uptake of extracellular vesicles. We discuss the underlying molecular mechanisms and the implications for a range of pathophysiological contexts, including hemostasis, immunity, tissue repair, cancer, and viral infection.

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Section: Integrin Adhesion Complexes Regulate Platelet and Leukocyte mentioning

confidence: 99%

Section: Integrin Crosstalk With the Endocytic Machinery Regulates Admentioning

confidence: 99%

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Nolte

Hoen

Margadant³

2021

Trends in Biochemical Sciences

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“…Using human leukocyte cell lines, this latter study then knocked down LCP1 and found that L-plastin depleted leukocytes were more adhesive, compared to controls, under conditions of flow. Taken together, these independent findings place L-plastin as a novel cytoplasmic suppressor of hematopoietic integrin adhesion operating through and ‘inside-out’ signaling mechanism (Nolte and Margadant 2020).…”

Section: Discussionmentioning

confidence: 90%

Follow that cell: leukocyte migration in L-plastin mutant zebrafish

Linehan

Zepeda

Mitchell

et al. 2022

Preprint

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Actin dynamics are important in motile cells such as leukocytes which form actin-rich extensions of the plasma membrane. L-plastin (LCP1) is a leukocyte-specific calcium-dependent actin-bundling protein that in mammals is known to affect immune cell migration and synapse formation. Previously, we generated CRISPR/Cas9 engineered zebrafish lacking L-plastin (lcp1-/-) and reported that they had somewhat reduced survival to adulthood, suggesting that lack of L-plastin might negatively affect the immune system. To test this hypothesis, we examined the distribution and migration of neutrophils and macrophages in the transparent tail of early zebrafish larva, using cell-specific markers and an established wound-migration assay. By crossing genotyped parents of our established L-plastin mutant lines, we were able to generate either 1:1 clutches of lcp1 heterozygous: homozygous siblings or 1:2:1 clutches representing all possible sibling combinations of wild type and mutant alleles. Knockout larvae were similar to their heterozygous siblings in having equal body sizes and comparable numbers of neutrophils in caudal hematopoietic tissue at 2 days post-fertilization (dpf), indicating no gross defect in neutrophil production or developmental migration. When stimulated by a tail wound all genotypes of neutrophils were equally migratory in a 2-hour window. However for macrophages we observed both migration defects and morphological differences. L-plastin knockout macrophages still homed to wounds but were slower, less directional and had a star-like morphology with many leading and trailing projections. In contrast, wild type macrophages were faster, more directional, and had a more streamlined, slug-like morphology. Overall, these findings show that in larval zebrafish L-plastin knockout primarily affects the macrophage response with possible consequences for organismal immunity. Consistent with these, we propose a model in which cytoplasmic L-plastin negatively regulates macrophage integrin adhesion by holding these transmembrane heterodimers in a 'clasped', inactive form.

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“…Recently, accumulating evidence demonstrates that ITGs are emerging as important regulators of immune cell signaling. [ 14 , 15 ] Thus, it is important to identify which subunits of ITG correlated with poor prognosis were mainly involved in the immune mechanism of LUAD. By analyzing the expression level of three ITGs of 3-ITG in immune cells associated with the recognition of tumor, it was found that only ITGAL had a strong correlation with a correlation coefficient (Cor) >0.5 and P < 0.05 ( Figure 7A–C ).…”

Section: Resultsmentioning

confidence: 99%

Lung adenocarcinoma-specific three-integrin signature contributes to poor outcomes by metastasis and immune escape pathways

Wang

Hou

Jin

et al. 2021

Journal of Translational Internal Medicine

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Background: Inhibitors targeting integrins (ITGs) are applied as a novel strategy for cancers including lung cancer; however, the heterogeneity of ITG subunits might explain why ITG-targeted inhibitors only show limited efficacy for a small group of lung cancer patients. Materials and methods: RNA-Seq data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were obtained from the TCGA database. Cox regression analysis was performed to construct the prognostic signature and generate the nomogram combined with pathologic stages (pStage). GEO datasets were used for verification. The related biological functions were analyzed by Gene Set Enrichment Analysis (GSEA) software and the TIMER database. Results: By Cox regression analysis of 30 ITG subunits, ITG subunit alpha 5 (ITGA5), ITG subunit alpha 6 (ITGA6), and ITG subunit alpha L (ITGAL) were identified as the prognostic factors in LUAD, which were included in the construction of a LUAD-specific 3-ITG signature. Following the calculation of risk score (RS) of each patient based on 3-ITG signature, patients with high RS in LUAD were found to exhibit worse prognosis, especially in early stage. Nomogram combined with RS and pStage could predict the prognosis of LUAD patients accurately. Mechanism exploration by GSEA showed that metastasis-related microenvironmental pathways were significantly enriched in the high-RS group. An elevated expression of ITGA5 was mainly associated with the promotion of cell migration and invasion, while the high expression of ITGAL had a strong positive correlation with the capability of recognizing and killing cancer cells. Conclusions: Three-ITG signature could improve the prediction ability combined with pStage in LUAD and might contribute to poor prognosis by metastasis and immune escape-related pathways.

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Activation and suppression of hematopoietic integrins in hemostasis and immunity

Abstract: Nolte and Margadant review the current understanding of the activation and inactivation of integrin receptors expressed by hematopoietic cells and the role of these conformational changes in modulating platelet and leukocyte function.

Cited by 23 publications

References 88 publications

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Follow that cell: leukocyte migration in L-plastin mutant zebrafish

Lung adenocarcinoma-specific three-integrin signature contributes to poor outcomes by metastasis and immune escape pathways

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