Platelet-derived growth factor β-receptor, transforming growth factor β type I receptor, and CD44 protein modulate each other's signaling and stability.
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.
['Porsch|Helena|H|', 'Mehić|Merima|M|', 'Olofsson|Berit|B|', 'Heldin|Paraskevi|P|', 'Heldin|Carl-Henrik|CH|']
D000818:Animals D000077214:Becaplermin D019556:COS Cells D002522:Chlorocebus aethiops D006801:Humans D018960:Hyaluronan Receptors D011485:Protein Binding D017346:Protein Serine-Threonine Kinases D055550:Protein Stability D020574:Proto-Oncogene Proteins c-sis D020797:Receptor, Platelet-Derived Growth Factor beta D000077293:Receptor, Transforming Growth Factor-beta Type I D018125:Receptors, Transforming Growth Factor beta D015398:Signal Transduction D016212:Transforming Growth Factor beta
CD44 PDGF Cell Signaling Cell Surface Receptor Cellular Regulation Transforming Growth Factor β (TGF-β)