Role of Endoproteolytic Processing in the Adhesive and Signaling Functions of αvβ5 Integrin

Abstract

Integrins are transmembrane glycoproteins, composed of noncovalently associated ␣ and ␤ subunits, that are involved in cell-extracellular matrix (ECM) 1 and cell-cell interactions (1). Many integrin ␣ chains undergo a post-translational endoproteolytic cleavage. The ␣ 3 , ␣ 5 , ␣ 6 , ␣ 7 , ␣ 8 , ␣ 9 , ␣ v , and ␣ IIb subunits are cleaved in the membrane-proximal extracellular region, resulting in a heavy chain that is disulfide-linked to a membrane spanning light chain (2). The ␣ 4 and ␣ E subunits can also be cleaved, but at unusual positions, near the middle and in the N-terminal region of the molecule, respectively (3, 4). Endoproteolytic cleavage of integrin ␣ subunits occurs at specific sites comprising pairs of basic amino acids.Post-translational proteolysis is a common mechanism required for the synthesis of biologically active proteins in bacteria, fungi, yeast, invertebrates, and mammals (5). However, the role of endoproteolytic cleavage of integrin ␣ subunits is not clear. The cleavage is conserved, not only in different ␣ chains but also across species, suggesting that it might be of functional importance. It has been established, by site-directed mutagenesis of cleavage sites, that uncleaved ␣ IIb ␤ 3 and ␣ 4

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

“…10,29 Control (empty vector, PDX0) and stably ␣1-PDX-transfected (PDX39P) HT29-D4 cells were described as previously reported. 10 In vitro haptotaxis assays were performed using modified Boyden chambers (Transwell, Costar, Cambridge, MA), as previously described. 30 In some experiments, cells were cultured for 48 hours in the presence of increasing concentrations of the furin inhibitor dec-RVKRcmk.…”

“…Arguably, this post-translational processing of the ␣ chain is not required for ligand binding, 10 -12 but is essential for the signaling function of ␣6␤1 and ␣v␤5 integrins. 10,13 Moreover, recent data suggest that the ␣6 subunit cleavage might be linked to the differentiation state of lens cells. 14 PCs are responsible for the biological activation of a variety of precursor proteins, including pro-hormones and their receptors and adhesion molecules.…”

“…␣1-PDX is a selective inhibitor of furin and, to a lesser extent, of PC5B 16 and blocks the convertase-dependent processing of various precursors, including integrins. 10 …”

“…[23][24][25] We have recently reported that the absence of endoproteolytic cleavage of ␣v integrins, by overexpression of ␣1-PDX in colonic cancer cells, has important consequences on signal transduction pathways leading to alterations in integrin function such as cell adhesion. 10 PCs inhibition also leads to reduced cell proliferation in vitro and delayed tumor growth in nude mice inoculated with tumor cells. 23 However, herein we demonstrate that PCs inhibition moderately reduced subcutaneous tumor growth but dramatically enhanced metastasis in immunosuppressed newborn rats.…”

“…␣1-PDX is a selective inhibitor of furin and, to a lesser extent, of PC5B 16 and blocks the convertase-dependent processing of various precursors, including integrins. 10,[17][18][19] Recent reports have suggested a possible role for PCs in tumorigenesis (for reviews, see references 15,20 ). Thus, furin expression levels correlate with invasiveness in human head and neck tumors and cell lines.…”