CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling

Abstract

CD44 is a facultative proteoglycan implicated in cell adhesion and trafficking, as well as in tumor survival and progression. We demonstrate here that CD44 heparan sulfate proteoglycan (CD44HSPG) recruits proteolytically active matrix metalloproteinase 7 (matrilysin, MMP-7) and heparin-binding epidermal growth factor precursor (pro-HB-EGF) to form a complex on the surface of tumor cell lines, postpartum uterine and lactating mammary gland epithelium, and uterine smooth muscle. The HB-EGF precursor within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to, among other events, cell survival. In CD44 −/− mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired. In both uterine and mammary epithelia of these mice, MMP-7 localization is altered and pro-HB-EGF processing as well as ErbB4 activation are decreased. Our observations provide a mechanism for the assembly and function of a cell surface complex composed of CD44HSPG, MMP 7, HB-EGF, and ErbB4 that may play an important role in the regulation of physiological tissue remodeling.

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

“…MMPs 7 and 11 are involved in apoptotic regulation through several pathways including FAS death receptor ligand cleavage and HB-EGF activation (Mitsiades et al, 2001;Wu et al, 2001;Yu et al, 2002). Additionally, MMPs cleave cell adhesion molecules such as Normal G1 G2 G3 E cadherin (Lochter et al, 1997), and modulate the immune response to tumours through chemokine deactivation (McQuibban et al, 2000(McQuibban et al, , 2001(McQuibban et al, , 2002 and T-lymphocyte suppression (Sheu et al, 2001).…”

Control of matrix metalloproteinase catalytic activity

“…Rather, proteinases, such as MMPs, would likely be anchored to the cell membrane, thereby maintaining a locally high enzyme concentration and targeting their catalytic activity to specific substrates within the pericellular space. In addition to the membrane-bound MMPs, several examples of specific cell-MMP interactions have been reported, such as the binding of MMP-2 to the α v β 3 integrin (Brooks et al, 1996), MMP-1 to the α 2 β 1 integrin Stricker et al, 2001), MMP-9 to CD44 (Yu and Stamenkovic, 2000), and MMP-7 to surface proteoglycans (Yu and Woessner, 2000;Yu et al, 2002), cholesterol (Yamamoto et al, 2006), and CD151 (Shiomi et al, 2005). As suggested for CD44 (Yu and Stamenkovic, 2000) and the α 2 β 1 integrin ), these membrane anchors may act as accessory factors that mediate both pro-enzyme activation and binding of both substrate and proteinase, thereby increasing the probability of proteolysis (Fig.…”

Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development

“…MMP-7 releases membrane-bound Fas ligand, thereby triggering apoptosis upon binding with the Fas receptor (Powell et al, 1999). On the other hand, MMP-7 can inhibit apoptosis by proteolytic generation of mature HB-EGF that promotes cell survival by stimulating the ErbB4 tyrosine kinase receptor (Yu et al, 2002). MMP-3 induces apoptosis when overexpressed in mammary epithelial cells (Alexander et al, 1996), whereas MMP-11 overexpression decreases spontaneous apoptosis in tumour xenografts (Wu et al, 2001).…”