Anti-integrin monoclonal antibodies

Byron, Adam; Humphries, Jonathan D.; Askari, Janet A.; Craig, Susan E.; Mould, A. Paul

doi:10.1242/jcs.056770

Cited by 154 publications

(186 citation statements)

References 13 publications

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“…However, the affinity state of the extendedclosed conformation was unclear. mAbs to integrins produced over the last 30 yr are a valuable resource, because their effects on integrin function on intact cells are well characterized (31). Previously, we have used the antibodies CBR LFA-1/2 and KIM127, which bind to the lower β 2 leg to show that extension is closely associated with β 2 integrin activation (8).…”

Section: Discussionmentioning

confidence: 99%

Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂

Chen

Xie

Nishida

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

102

145

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Negative stain electron microscopy (EM) and adhesion assays show that α X β 2 integrin activation requires headpiece opening as well as extension. An extension-inducing Fab to the β 2 leg, in combination with representative activating and inhibitory Fabs, were examined for effect on the equilibrium between the open and closed headpiece conformations. The two activating Fabs stabilized the open headpiece conformation. Conversely, two different inhibitory Fabs stabilized the closed headpiece conformation. Adhesion assays revealed that αXβ 2 in the extended-open headpiece conformation had high affinity for ligand, whereas both the bent conformation and the extended-closed headpiece conformation represented the low affinity state. Intermediate integrin affinity appears to result not from a single conformational state, but from a mixture of equilibrating conformational states.

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Section: Discussionmentioning

confidence: 99%

Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂

Chen

Xie

Nishida

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

102

145

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“…the inhibitory antibody mAb13 and the stimulating antibody 12G10 bind to the same integrin b1 epitope (Mould et al, 1996;Byron et al, 2010) provides strong evidence that the antibodymediated steric hindrance is not the mechanism by which mAb13 inhibits invasome formation. Furthermore, mAb13 was shown to preferentially bind to and stabilize the bent, inactive integrin b1 conformation and was suggested to induce a conformational change from the open to the closed integrin b1 conformation in ligand-occupied, extend integrins.…”

Section: Discussionmentioning

confidence: 99%

Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake

Truttmann

Misselwitz

Huser

et al. 2011

Journal of Cell Science

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SummaryThe VirB/D4 type IV secretion system (T4SS) of the bacterial pathogen Bartonella henselae (Bhe) translocates seven effector proteins (BepA-BepG) into human cells that subvert host cellular functions. Two redundant pathways dependent on BepG or the combination of BepC and BepF trigger the formation of a bacterial uptake structure termed the invasome. Invasome formation is a multi-step process consisting of bacterial adherence, effector translocation, aggregation of bacteria on the cell surface and engulfment, and eventually, complete internalization of the bacterial aggregate occurs in an F-actin-dependent manner. In the present study, we show that Bhe-triggered invasome formation depends on integrin-b1-mediated signaling cascades that enable assembly of the F-actin invasome structure. We demonstrate that Bhe interacts with integrin b1 in a fibronectin-and VirB/D4 T4SS-independent manner and that activated integrin b1 is essential for both effector translocation and the actin rearrangements leading to invasome formation. Furthermore, we show that talin1, but not talin2, is required for inside-out activation of integrin b1 during invasome formation. Finally, integrin-b1-mediated outside-in signaling by FAK, Src, paxillin and vinculin is necessary for invasome formation. This is the first example of a bacterial entry process that fully exploits the bi-directional signaling capacity of integrin receptors in a talin1-specific manner.

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“…Many monoclonal antibodies have been raised that are reactive towards a variety of conformations of 1-integrins (Mould, 1996;Humphries, 2000;Byron et al, 2009). Our initial aim was to use a selection of these antibodies to determine the folding, assembly and trafficking of integrins.…”

Section: Probing the Folding And Assembly Of Integrins Using Monoclonmentioning

confidence: 99%

Divalent cations regulate the folding and activation status of integrins during their intracellular trafficking

Tiwari

Askari

Humphries

et al. 2011

Journal of Cell Science

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Integrins are divalent cation-dependent, αβ heterodimeric adhesion receptors that control many fundamental aspects of cell behaviour by bi-directional signalling between the extracellular matrix and intracellular cytoskeleton. The activation state of cell surface integrins is tightly regulated by divalent cation occupancy of the ligand-binding pocket and by interaction with cytoplasmic adaptor proteins, such as talin. These agents elicit gross conformational changes across the entire molecule, which specify the activation state. Much less is known about the activation state of newly synthesised integrins or the role of cations during the early folding and trafficking of integrins. Here we use a number of well-characterised, conformation-specific antibodies to demonstrate that β1-integrins adopt the bent, inactive conformation after assembly with α-integrins in the endoplasmic reticulum. Folding and assembly are totally dependent on the binding of Ca2+ ions. In addition, Ca2+ binding prevents integrin activation before its arrival at the cell surface. Activation at the cell surface occurs only following displacement of Ca2+ with Mg2+ or Mn2+. These results demonstrate the essential roles played by divalent cations to facilitate folding of the β-integrin subunit, to prevent inappropriate intracellular integrin signalling, and to activate ligand binding and signalling at the cell surface.

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Anti-integrin monoclonal antibodies

Cited by 154 publications

References 13 publications

Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂

Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂

Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake

Divalent cations regulate the folding and activation status of integrins during their intracellular trafficking

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Anti-integrin monoclonal antibodies

Cited by 154 publications

References 13 publications

Requirement of open headpiece conformation for activation of leukocyte integrin αXβ2

Requirement of open headpiece conformation for activation of leukocyte integrin αXβ2

Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake

Divalent cations regulate the folding and activation status of integrins during their intracellular trafficking

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Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂

Requirement of open headpiece conformation for activation of leukocyte integrin α_Xβ₂