Macropinocytosis of the PDGF β-receptor promotes fibroblast transformation by H-RasG12V
2012 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 13, 2571-2582 p.Article in journal (Refereed) Published
Receptor tyrosine kinase (RTK) signaling is frequently increased in tumor cells, sometimes as a result of decreased receptor down-regulation. To what extent the endocytic trafficking routes can contribute to such RTK hyper-activation 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 synergized in stimulating PI 3-kinase activity, leading to receptor macropinocytosis. PDGFRβ macropinocytosis was both necessary and sufficient for enhanced receptor activation. Blocking macropinocytosis by inhibition of phosphatidylinositol (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 non-transformed cells. Simultaneous stimulation with PDGF-BB and epidermal growth factor (EGF) promoted macropinocytosis of both receptors and increased their activation in non-transformed cells. We propose that H-Ras transformation promotes tumor progression by enhancing growth factor receptor signaling as a result of increased receptor macropinocytosis.
Place, publisher, year, edition, pages
2012. Vol. 23, no 13, 2571-2582 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-175983DOI: 10.1091/mbc.E11-04-0317ISI: 000306287400017PubMedID: 22573884OAI: oai:DiVA.org:uu-175983DiVA: diva2:533777