Protein disulfide isomerase mediates integrin‐dependent adhesion

Abstract

Cell adhesion is mediated by the integrin adhesion receptors. Receptor^ligand interaction involves conformational changes in the receptor, but the underlying mechanism remains unclear. Our earlier work implied a role for sulfhydryls in integrin response to ligand binding in the intact blood platelet. We now show that non-penetrating blockers of free sulfhydryls inhibit L L 1 and L L 3 integrin-mediated platelet adhesion regardless of the affinity state of the integrin. Removal of the inhibitors prior to adhesion fully restores adhesion despite the irreversible nature of inhibitor^thiol interaction, indicating sulfhydryl exposure in response to adhesion. We further show that blocking protein disulfide isomerase (PDI) inhibits adhesion. These data indicate that: (a) ecto-sulfhydryls are necessary for integrinmediated platelet adhesion; (b) disulfide exchange takes place during this process; (c) surface PDI is involved in integrinmediated adhesion. ß

Protein Disulfide Isomerase-2 of Arabidopsis Mediates Protein Folding and Localizes to Both the Secretory Pathway and Nucleus, Where It Interacts with Maternal Effect Embryo Arrest Factor

“…PDIs are required for cell viability (Ferrari and Soling, 1999) and differentiation (Ohtani et al, 1993), ion uptake (Honscha et al, 1993), regulating transcription (Markus and Benezra, 1999) and are found in the nucleus, cytoplasm, ER, mitochondria, and extracellular milieu (Couet et al, 1996;Lahav et al, 2000;Rigobello et al, 2001;Turano et al, 2002;Wilson et al, 1998). Recently, human PDI was found to bind signal peptide peptidase and unfold target proteins, leading to their dislocation from the ER to the cytoplasm and degradation by the ubiquitin-proteasome system, which is a process known as ER-associated degradation (ERAD) (Lee et al, 2010).…”

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

“…4), while sheep anti-FXIIIA2B2 antibody that does not interfere with PDI activity had no effect on adhesion. Moreover, the anti-PDI activity of rabbit anti FXIIA antibody reduced the adhesion of untreated platelets, probably by inhibiting surface-associated PDI on the platelets which is required for intact platelet adhesion (11,12).…”

“…In the present study, on the basis of our earlier findings that PDI plays a mediatory role in platelet adhesion [11][12][13] and that FXIIIA exerts PDI activity [10], we sought to examine the relative contributions of FXIII PDI or transglutaminase activity to platelet adhesion to fibrinogen.…”

“…Cellsurface-localized, membrane-bound PDI is essential for sustaining the binding of fibrinogen, fibronectin, and collagen to platelet integrins αIIbβ3, α5β1, and α2β1, respectively [11,12], thereby regulating platelet adhesion [11,12] and aggregation [13]. PDI also regulates the activity of L-selectin, a cell-adhesion molecule found on leukocytes [14].…”

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

“…[44][45][46][47] Some evidence suggests that PDI may also be localized to the cell membrane in tumor cells and there modulate integrin-dependent adhesion and sensitivity to chemotherapy. [48][49][50] To examine whether PDI is immunogenic in cancer patients, we established an ELISA with recombinant full-length human protein and evaluated sera from 46 metastatic melanoma, 22 metastatic non-small cell lung carcinoma, 2 metastatic ovarian carcinoma, and 12 acute myeloid leukemia patients who were enrolled on phase I clinical trials of vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF. We used a pan-human IgG secondary antibody to measure preferentially those isotypes dependent upon CD4 ϩ T-cell help for class switching.…”