CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling.
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.
Yu
Wei-Hsuan
WH
Molecular Pathology Unit, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129, USA.
Woessner
J Frederick
JF
McNeish
John D
JD
Stamenkovic
Ivan
I
D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000502:physiology*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D018960:Hyaluronan Receptors / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010766:Phosphorylation; D049590:Postpartum Period; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000378:metabolism; D066247:Receptor, ErbB-4; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014599:Uterus / Q000502:physiology*
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D020783:Matrix Metalloproteinase 7