title: Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling.
abstract: Platelet-derived growth factor receptor β (PDGFRβ) is a receptor tyrosine kinase which upon activation by PDGF-BB stimulates cell proliferation, migration and angiogenesis. Ligand binding induces intracellular signaling cascades but also internalization of the receptor, eventually resulting in its lysosomal degradation. However, endocytic trafficking of receptors often modulates their downstream signaling. We previously reported that internalization of PDGFRβ occurs via dynamin-dependent and -independent pathways but their further molecular determinants remained unknown. Here we show that, in human fibroblasts expressing endogenous PDGFRβ and stimulated with 50 ng/ml PDGF-BB, ligand-receptor uptake proceeds via the parallel routes of clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE). CME involves the canonical AP2 complex as a clathrin adaptor, while CIE requires RhoA-ROCK, Cdc42 and galectin-3, the latter indicating lectin-mediated internalization via clathrin-independent carriers (CLICs). Although different uptake routes appear to be partly interdependent, they cannot fully substitute for each other. Strikingly, inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRβ. Our data indicate that multiple routes of internalization of PDGFRβ contribute to a transcriptional and mitogenic response of cells to PDGF.
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Jastrzębski
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.
authors.forename: Daria
authors.initials: D
authors.lastname: Zdżalik-Bielecka
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Mamińska
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Kalaidzidis
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Carina
authors.initials: C
authors.lastname: Hellberg
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland miaczynska@iimcb.gov.pl.
authors.forename: Marta
authors.identifier: 0000-0003-0031-5267
authors.initials: M
authors.lastname: Miaczynska
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects* / Q000235:genetics; D037502:Galectin 3 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D033962:Adaptor Protein Complex 2; D002966:Clathrin; D037502:Galectin 3; D018960:Hyaluronan Receptors; D010982:Platelet-Derived Growth Factor; D050796:STAT3 Transcription Factor; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta; D054460:rho-Associated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D034281:Dynamins
keywords: Endocytosis; PDGF-BB; PDGFRβ; Platelet-derived growth factor BB; Platelet-derived growth factor receptor β; Rho GTPase; STAT3; Signal transducer and activator of transcription 3