title: Macropinocytosis of the PDGF β-receptor promotes fibroblast transformation by H-RasG12V.
abstract: Receptor tyrosine kinase (RTK) signaling is frequently increased in tumor cells, sometimes as a result of decreased receptor down-regulation. The extent to which the endocytic trafficking routes can contribute to such RTK hyperactivation is unclear. Here, we show for the first time that fibroblast transformation by H-RasG12V induces the internalization of platelet-derived growth factor β-receptor (PDGFRβ) by macropinocytosis, enhancing its signaling activity and increasing anchorage-independent proliferation. H-RasG12V transformation and PDGFRβ activation were synergistic in stimulating phosphatidylinositol (PI) 3-kinase activity, leading to receptor macropinocytosis. PDGFRβ macropinocytosis was both necessary and sufficient for enhanced receptor activation. Blocking macropinocytosis by inhibition of PI 3-kinase prevented the increase in receptor activity in transformed cells. Conversely, increasing macropinocytosis by Rabankyrin-5 overexpression was sufficient to enhance PDGFRβ activation in nontransformed cells. Simultaneous stimulation with PDGF-BB and epidermal growth factor promoted macropinocytosis of both receptors and increased their activation in nontransformed cells. We propose that H-Ras transformation promotes tumor progression by enhancing growth factor receptor signaling as a result of increased receptor macropinocytosis.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Schmees
authors.forename: R
authors.initials: R
authors.lastname: Villaseñor
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Zerial
authors.forename: C-H
authors.initials: CH
authors.lastname: Heldin
authors.forename: C
authors.initials: C
authors.lastname: Hellberg
mesh_terms: D000077214:Becaplermin; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D010766:Phosphorylation; D010873:Pinocytosis; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)