The Role of Integrins in Health and Disease—Series 2

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 2465

Special Issue Editor

Department of Dermatology, School of Medicine, University of California–Davis, 4645 Second Ave., Research III Suite 3300, Sacramento, CA 95817, USA
Interests: integrin-growth factor crosstalk; regulation of integrin activation; identification of new integrin ligands
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Special Issue Information

Dear Colleagues,

In the 1980s, integrins were identified as cell adhesion receptors that recognize extracellular ligands (e.g., fibronectin, fibrinogen, laminin, and collagen) and cell surface ligands (e.g., VCAM-1, and ICAM-1). Currently, 18 alpha subunits, 8 beta subunits, and altogether 24 heterodimers have been identified. Integrins are involved in many biological processes and in the pathogenesis of diseases. I was involved in the original identification of beta1 integrins and the cloning of three alpha subunits (alpha2, alpha3, and alpha4), and identified several extracellular matrix ligands at the Dana–Farber Cancer Institute with Dr. Martin Hemler in the 1980s. I focused on the structure–function studies of several integrins (how integrins interact with ligands and how integrins are activated) in the 1990s at the Scripps Research Institute. I then identified many integrin ligands (mostly growth factors) and studied how integrins crosstalk with growth factor signaling. We propose that several growth factors directly bind to integrins and induce the integrin–growth factor–growth factor receptor ternary complex. We recently found that several newly identified integrin ligands (e.g., fractalkine) directly bind to integrin and allosterically activate integrins. I have witnessed the growth of this field for the past 40 years, almost from the beginning. Now, the field is so diverse that it is not easy to understand the whole picture of integrin functions. It is also possible that current models of integrin functions may not be correct. Therefore, this Special Issue will provide the current state of the field by collecting the opinions of as many experts as possible.

Prof. Dr. Yoshikazu Takada
Guest Editor

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Keywords

  • integrins and diseases
  • integrin activation
  • integrin–ECM interaction
  • integrin–growth factor crosstalk

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Published Papers (2 papers)

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Research

14 pages, 3310 KiB  
Article
CD40L Activates Platelet Integrin αIIbβ3 by Binding to the Allosteric Site (Site 2) in a KGD-Independent Manner and HIGM1 Mutations Are Clustered in the Integrin-Binding Sites of CD40L
by Yoko K. Takada, Michiko Shimoda and Yoshikazu Takada
Cells 2023, 12(15), 1977; https://doi.org/10.3390/cells12151977 - 31 Jul 2023
Cited by 1 | Viewed by 666
Abstract
CD40L is expressed in activated T cells, and it plays a major role in immune response and is a major therapeutic target for inflammation. High IgM syndrome type 1 (HIGM1) is a congenital functional defect in CD40L/CD40 signaling due to defective CD40L. CD40L [...] Read more.
CD40L is expressed in activated T cells, and it plays a major role in immune response and is a major therapeutic target for inflammation. High IgM syndrome type 1 (HIGM1) is a congenital functional defect in CD40L/CD40 signaling due to defective CD40L. CD40L is also stored in platelet granules and transported to the surface upon platelet activation. Platelet integrin αIIbβ3 is known to bind to fibrinogen and activation of αIIbβ3 is a key event that triggers platelet aggregation. Also, the KGD motif is critical for αIIbβ3 binding and the interaction stabilizes thrombus. Previous studies showed that CD40L binds to and activates integrins αvβ3 and α5β1 and that HIGM1 mutations are clustered in the integrin-binding sites. However, the specifics of CD40L binding to αIIbβ3 were unclear. Here, we show that CD40L binds to αIIbβ3 in a KGD-independent manner using CD40L that lacks the KGD motif. Two HIGM1 mutants, S128E/E129G and L155P, reduced the binding of CD40L to the classical ligand-binding site (site 1) of αIIbβ3, indicating that αIIbβ3 binds to the outer surface of CD40L trimer. Also, CD40L bound to the allosteric site (site 2) of αIIbβ3 and allosterically activated αIIbβ3 without inside-out signaling. Two HIMG1 mutants, K143T and G144E, on the surface of trimeric CD40L suppressed CD40L-induced αIIbβ3 activation. These findings suggest that CD40L binds to αIIbβ3 in a manner different from that of αvβ3 and α5β1 and induces αIIbβ3 activation. HIGM1 mutations are clustered in αIIbβ3 binding sites in CD40L and are predicted to suppress thrombus formation and immune responses through αIIbβ3. Full article
(This article belongs to the Special Issue The Role of Integrins in Health and Disease—Series 2)
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18 pages, 2975 KiB  
Article
Pro-Inflammatory Chemokines CCL5, CXCL12, and CX3CL1 Bind to and Activate Platelet Integrin αIIbβ3 in an Allosteric Manner
by Yoko K. Takada, Masaaki Fujita and Yoshikazu Takada
Cells 2022, 11(19), 3059; https://doi.org/10.3390/cells11193059 - 29 Sep 2022
Cited by 4 | Viewed by 1492
Abstract
Activation of platelet integrin αIIbβ3, a key event for hemostasis and thrombus formation, is known to be mediated exclusively by inside-out signaling. We showed that inflammatory chemokines CX3CL1 and CXCL12 in previous studies, and CCL5 in this study, bound to the allosteric binding [...] Read more.
Activation of platelet integrin αIIbβ3, a key event for hemostasis and thrombus formation, is known to be mediated exclusively by inside-out signaling. We showed that inflammatory chemokines CX3CL1 and CXCL12 in previous studies, and CCL5 in this study, bound to the allosteric binding site (site 2) of vascular integrin αvβ3, in addition to the classical ligand binding site (site 1), and allosterically activated integrins independent of inside-out signaling. Since αIIbβ3 is exposed to inflammatory chemokines at increased concentrations during inflammation (e.g., cytokine/chemokine storm) and platelet activation, we hypothesized that these chemokines bind to and activate αIIbβ3 in an allosteric activation mechanism. We found that these chemokines bound to αIIbβ3. Notably, they activated soluble αIIbβ3 in 1 mM Ca2+ by binding to site 2. They activated cell-surface αIIbβ3 on CHO cells, which lack machinery for inside-out signaling or chemokine receptors, quickly (<1 min) and at low concentrations (1–10 ng/mL) compared to activation of soluble αIIbβ3, probably because chemokines bind to cell surface proteoglycans. Furthermore, activation of αIIbβ3 by the chemokines was several times more potent than 1 mM Mn2+. We propose that CCL5 and CXCL12 (stored in platelet granules) may allosterically activate αIIbβ3 upon platelet activation and trigger platelet aggregation. Transmembrane CX3CL1 on activated endothelial cells may mediate platelet–endothelial interaction by binding to and activating αIIbβ3. Additionally, these chemokines in circulation over-produced during inflammation may trigger αIIbβ3 activation, which is a possible missing link between inflammation and thrombosis. Full article
(This article belongs to the Special Issue The Role of Integrins in Health and Disease—Series 2)
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