Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates α4 integrins

Imai, Yumiko; Park, Eun Jeong; Peer, Dan; Peixoto, António; Cheng, George; Andrian, Ulrich H. von; Carman, Christopher V.; Shimaoka, Motomu

doi:10.1182/blood-2008-03-144543

Cited by 30 publications

(29 citation statements)

References 38 publications

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“…Although it was not studied in these patients, our data here suggest that a IIb b 3 integrin with a IIb -R995 or b 3 -D723 mutations might be more responsive to agonist stimulation leading to more platelet aggregation than in wild type, which might simultaneously cause a reduction in the amount of platelets in blood. An equivalent Arg to Ala mutation of a 4 integrin CT has been found to aberrantly activate a 4 integrin in genetic knock-in mice (Imai et al, 2008). We also found that the equivalent b 2 -D709A mutation renders a L b 2 integrin hyper-responsive to talin-1-head-induced activation.…”

Section: Icam-1 Binding (Nomalized Mfi)supporting

confidence: 52%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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Section: Icam-1 Binding (Nomalized Mfi)supporting

confidence: 52%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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“…LFA-1 also supports monocyte firm adhesion and crawling in quiescent condition, whereas Mac-1 is responsible for TNF-a-stimulated monocyte crawling (16). Multiple functional states of LFA-1 with different affinities are required for lymphocyte rolling, adhesion, and crawling because no Mac-1 molecules are presented onto lymphocyte surface (17)(18)(19)(20). These observations bring up a question why the two structurally similar b 2 integrins behave distinctly in leukocyte recruitment and what the underlying mechanisms are.…”

mentioning

confidence: 89%

“…Although a body of evidences has been found to focus on the functional differences between Mac-1 and LFA-1 using in vivo, ex vivo, and in vitro measurements (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), it is still hard to provide a mechanistic insight. One way to elucidate the underlying mechanisms is to quantify the binding kinetics because it determines the on-and off-rates and binding affinity of interacting molecules.…”

mentioning

confidence: 99%

Distinct Binding Affinities of Mac-1 and LFA-1 in Neutrophil Activation

Lü

et al. 2013

The Journal of Immunology

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Macrophage-1 Ag (Mac-1) and lymphocyte function-associated Ag-1 (LFA-1), two β2 integrins expressed on neutrophils (PMNs), mediate PMN recruitment cascade by binding to intercellular adhesive molecule 1. Distinct functions of LFA-1–initiating PMN slow rolling and firm adhesion but Mac-1–mediating cell crawling are assumed to be governed by the differences in their binding affinities and kinetic rates. In this study, we applied an adhesion frequency approach to compare their kinetics in the quiescent and activated states using three molecular systems, constitutively expressed receptors on PMNs, wild-type and high-affinity (HA) full-length constructs transfected on 293T cells, and wild-type and HA recombinant extracellular constructs. Data indicate that the difference in binding affinity between Mac-1 and LFA-1 is on-rate dominated with slightly or moderately varied off-rate. This finding was further confirmed when both β2 integrins were activated by chemokines (fMLF or IL-8), divalent cations (Mg2+ or Mn2+), or disulfide bond lockage on an HA state. Structural analyses reveal that such the kinetics difference is likely attributed to the distinct conformations at the interface of Mac-1 or LFA-1 and intercellular adhesive molecule 1. This work furthers the understandings in the kinetic differences between Mac-1 and LFA-1 and in their biological correlations with molecular activation and structural bases.

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“…This phenotype resembles the excessive intraluminal adhesion and defective migration of leukocytes in knock-in mice expressing constitutively active forms of integrin a L b 2 39,40 or a 4 b 1 and a 4 b 7 . 41 In WT mice, extravasating leukocytes exhibit delayed detachment of elongated uropods from the subendothelial layer before moving away from venules. 42 In EHCgp130 2/2 mice, by contrast, most neutrophils that exited the lumen remained between endothelial cells and pericytes, consistent with persistent excessive adhesion on the abluminal surface.…”

Section: Discussionmentioning

confidence: 99%

Elevated CXCL1 expression in gp130-deficient endothelial cells impairs neutrophil migration in mice

Yao

Yago

Shao

et al. 2013

Blood

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Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates α4 integrins

Cited by 30 publications

References 38 publications

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Distinct Binding Affinities of Mac-1 and LFA-1 in Neutrophil Activation

Elevated CXCL1 expression in gp130-deficient endothelial cells impairs neutrophil migration in mice

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