title: CD44 Influences Fibroblast Behaviors Via Modulation of Cell-Cell and Cell-Matrix Interactions, Affecting Survivin and Hippo Pathways.
abstract: CD44 has been studied in a wide variety of cell types, in a diverse array of cell behaviors and in a diverse range of signaling pathways. We now document a role for CD44 in mediating fibroblast behaviors via regulation of N-cadherin, extracellular matrix expression, Survivin and the Hippo pathway. Here, we report our findings on the roles of CD44 in modulating proliferation, apoptosis, migration and invasion of murine wild-type (WT-FB) and CD44 knockout dermal fibroblasts (CD44KO-FB). As we have documented in microvascular endothelial cells lacking CD44, we found persistent increased proliferation, reduced activation of cleaved caspase 3, increased initial attachment, but decreased strength of cell attachment in high cell density, post confluent CD44KO-FB cultures. Additionally, we found that siRNA knock-down of CD44 mimicked the behaviors of CD44KO-FB, restoring the decreases in N-cadherin, collagen type I, fibronectin, Survivin, nuclear fractions of YAP and phospho-YAP and decreased levels of cleaved caspase 3 to the levels observed in CD44KO-FB. Interestingly, plating CD44KO-FB on collagen type I or fibronectin resulted in significant decreases in secondary proliferation rates compared to plating cells on non-coated dishes, consistent with increased cell adhesion compared to their effects on WT-FB. Lastly, siRNA knockdown of CD44 in WT-FB resulted in increased fibroblast migration compared to WT-FB, albeit at reduced rates compared to CD44KO-FB. These results are consistent with CD44's pivotal role in modulating several diverse behaviors important for adhesion, proliferation, apoptosis, migration and invasion during development, growth, repair, maintenance and regression of a wide variety of mesenchymal tissues.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.|Division of Cancer Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology*; D000090683:Hippo Signaling Pathway; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D015820:Cadherins; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin; D017346:Protein Serine-Threonine Kinases