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PMID: 22573884 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Macropinocytosis of the PDGF β-receptor promotes fibroblast transformation by H-RasG12V.

Molecular biology of the cell ·Vol. 23 ·No. 13 ·2012-07-00 ·Pages 2571-82

Schmees C, Villaseñor R, Zheng W, Ma H, Zerial M, Heldin CH, Hellberg C

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.

MeSH Terms
Becaplermin Cell Adhesion Cell Proliferation Cell Transformation, Neoplastic/genetics Cells, Cultured Epidermal Growth Factor/physiology ErbB Receptors/metabolism Fibroblasts/metabolism,physiology Humans Mutation, Missense Phosphorylation Pinocytosis Protein Processing, Post-Translational Protein Transport Proto-Oncogene Proteins c-sis/physiology Proto-Oncogene Proteins p21(ras)/genetics Receptor, Platelet-Derived Growth Factor beta/metabolism Signal Transduction Transport Vesicles/metabolism
Chemicals
Proto-Oncogene Proteins c-sis Becaplermin Epidermal Growth Factor ErbB Receptors Receptor, Platelet-Derived Growth Factor beta HRAS protein, human Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Schmees C
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Villaseñor R
Zheng W
Ma H
Zerial M
Heldin C-H
Hellberg C
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.E11-04-0317
Published
2012-07-00
Epub
2012-00-09
Pages
2571-82
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC3386220
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.E11-04-0317 PMC Full Text View journal details
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