Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells.
Constitutive expression of Wnt1 and Wnt5a in HC11 mammary cells led to elevated TCF transcriptional activity. Intriguingly, Wnt-expressing cells also displayed activation of ErbB1 and mitogen-activated protein kinase (MAPK), in contrast to control HC11 cells, which did not. Furthermore, conditioned media harvested from Wnt-expressing cells stimulated ErbB1 and the MAPK cascade when added to control cells. This process was rapid and could be blocked by an ErbB1 antibody that interferes with ligand binding and by matrix metalloproteinase (MMP) inhibitors. These results suggest that in mammary cells Wnt binding to its receptor, Frizzled (Fz), transactivates ErbB1, probably by MMP-mediated release of soluble ErbB1 ligands. Importantly, Wnt-transactivated ErbB1 was responsible for MAPK activation and the increased levels of cyclin D1 present in the Wnt-expressing HC11 cells. Our finding that Wnts transactivate ErbB1 in addition to stimulating the prototypic beta-catenin/TCF pathway may help to explain why wnt1 is a potent oncogene in the mammary gland.
Civenni
Gianluca
G
Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Holbro
Thomas
T
Hynes
Nancy E
NE
D001940:Breast / Q000378:metabolism*; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D011518:Proto-Oncogene Proteins; C495247:WNT1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D019938:Cyclin D1; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases