title: Platelet-derived growth factor β-receptor, transforming growth factor β type I receptor, and CD44 protein modulate each other's signaling and stability.
abstract: Growth factors, such as platelet-derived growth factor BB (PDGF-BB) and transforming growth factor β (TGFβ), are key regulators of cellular functions, including proliferation, migration, and differentiation. Growth factor signaling is modulated by context-dependent cross-talk between different signaling pathways. We demonstrate in this study that PDGF-BB induces phosphorylation of Smad2, a downstream mediator of the canonical TGFβ pathway, in primary dermal fibroblasts. The PDGF-BB-mediated Smad2 phosphorylation was dependent on the kinase activities of both TGFβ type I receptor (TβRI) and PDGF β-receptor (PDGFRβ), and it was prevented by inhibitory antibodies against TGFβ. Inhibition of the activity of the TβRI kinase greatly reduced the PDGF-BB-dependent migration in dermal fibroblasts. Moreover, we demonstrate that the receptors for PDGF-BB and TGFβ interact physically in primary dermal fibroblasts and that stimulation with PDGF-BB induces internalization not only of PDGFRβ but also of TβRI. In addition, silencing of PDGFRβ by siRNA decreased the stability of TβRI and delayed TGFβ-induced signaling. We further show that the hyaluronan receptor CD44 interacts with both PDGFRβ and TβRI. Depletion of CD44 by siRNA increased signaling via PDGFRβ and TβRI by stabilizing the receptor proteins. Our data suggest that cross-talk between PDGFRβ and TβRI occurs in dermal fibroblasts and that CD44 negatively modulates signaling via these receptors.
authors.affiliation: From the Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 595, SE-75124 Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Porsch
authors.affiliation: From the Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 595, SE-75124 Uppsala, Sweden.
authors.forename: Merima
authors.initials: M
authors.lastname: Mehić
authors.affiliation: From the Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 595, SE-75124 Uppsala, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Olofsson
authors.affiliation: From the Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 595, SE-75124 Uppsala, Sweden Evi.Heldin@LICR.uu.se.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Heldin
authors.affiliation: From the Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 595, SE-75124 Uppsala, Sweden C-H.Heldin@LICR.uu.se.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
mesh_terms: D000818:Animals; D000077214:Becaplermin; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D020574:Proto-Oncogene Proteins c-sis; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: CD44; Cell Signaling; Cell Surface Receptor; Cellular Regulation; PDGF; Transforming Growth Factor β (TGF-β)