Multiple non-catalytic ADAMs are novel integrin α4 ligands

Abstract

The ADAM (a disintegrin and metalloprotease) protein family uniquely exhibits both catalytic and adhesive properties. In the well-defined process of ectodomain shedding, ADAMs transform latent, cell-bound substrates into soluble, biologically active derivatives to regulate a spectrum of normal and pathological processes. In contrast, the integrin ligand properties of ADAMs are not fully understood. Emerging models posit that ADAM-integrin interactions regulate shedding activity by localizing or sequestering the ADAM sheddase. Interestingly, 8 of the 21 human ADAMs are predicted to be catalytically inactive. Unlike their catalytically active counterparts, integrin recognition of these "dead" enzymes has not been largely reported. The present study delineates the integrin ligand properties of a group of non-catalytic ADAMs. Here we report that human ADAM11, ADAM23, and ADAM29 selectively support integrin α4-dependent cell adhesion. This is the first demonstration that the disintegrin-like domains of multiple catalytically inactive ADAMs are ligands for a select subset of integrin receptors that also recognize catalytically active ADAMs.

A disintegrin and metalloprotease 23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

“…Additionally, downregulation of ADAM23 in a side population of lung adenocarcinoma cells contributed to the CSC phenotype, supposedly by promoting activity of α V β 3 integrin . These findings support the hypothesis that by binding to integrins, namely α V β 3 and α4 and/or other cell‐surface molecules, ADAM23 can act as a mediator of intercellular association and participate in facilitating EMT in cancer cells …”

“…57 These findings support the hypothesis that by binding to integrins, namely α V β 3 and α4 and/or other cell-surface molecules, ADAM23 can act as a mediator of intercellular association and participate in facilitating EMT in cancer cells. 31,32 To the best of our knowledge, this is the and Ludovit Gaspar for their excellent technical assistance. We are grateful to all patients and controls for their participation in the study.…”

“…Through its disintegrin‐like domain, ADAM23 may function as an adhesion molecule involved in α V β 3 ‐mediated cell interactions occurring in normal and pathological processes . In addition to α V β 3 , the disintegrin domain of ADAM23 also ensures specific binding to other integrins such as α 4 β 1 and α 4 β 7 . Based on its adhesion function, ADAM23 is considered a possible tumor suppressor gene which is frequently downregulated in various types of malignancies including breast, head and neck, lung, gastric, brain and ovarian cancers .…”

“…30 In addition to α V β 3 , the disintegrin domain of ADAM23 also ensures specific binding to other integrins such as α 4 β 1 and α 4 β 7 . 31,32 Based on its adhesion function, ADAM23 is considered a possible tumor suppressor gene which is frequently downregulated in various types of malignancies including breast, head and neck, lung, gastric, brain and ovarian cancers. [33][34][35][36][37][38] Its epigenetic silencing through promoter hypermethylation 31,33 and association between ADAM23 methylation and clinical characteristics has been previously observed in BC patients.…”

How tetraspanin-mediated cell entry of SARS-CoV-2 can dysregulate the shedding of the ACE2 receptor by ADAM17

“…The superior fit of Phe 176 between the contiguous residues Thr 541 and Cys 542 , located on the turn of the disintegrin loop of ADAM17, is reflected in a 50% increase in the BSA of phenylalanine. This loop has been identified as the interface for attachment of ADAM17 to multiple integrins [ 45 ], and apart from Thr 541 and Cys 542 the loop remains exposed in the predicted CD9/ADAM17 complex, and so capable of further complexation to yield a ternary α5β1/CD9/ADAM17 complex, Fig. 4 .…”