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First published online 12 February 2008
doi: 10.1242/jcs.016964

Journal of Cell Science 121, 695-705 (2008)
Published by The Company of Biologists 2008
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Research Article

The R-Ras interaction partner ORP3 regulates cell adhesion

Markku Lehto1,2, Mikko I. Mäyränpää3,4, Teijo Pellinen5, Pekka Ihalmo2, Sanna Lehtonen6, Petri T. Kovanen3, Per-Henrik Groop2, Johanna Ivaska5 and Vesa M. Olkkonen1,*

1 Department of Molecular Medicine, National Public Health Institute, Biomedicum, FI-00251 Helsinki, Finland
2 Folkhälsan Institute of Genetics, Folkhälsan Research Centre Biomedicum, Biomedicum, University of Helsinki, Helsinki, Finland
3 Wihuri Research Institute, Helsinki, Finland
4 Department of Forensic Medicine, University of Helsinki, Finland
5 VTT Medical Biotechnology, Turku, Finland
6 Department of Pathology, Haartman Institute, University of Helsinki, Finland

* Author for correspondence (e-mail: vesa.olkkonen{at}ktl.fi)

Accepted 19 November 2007

Oxysterol-binding protein (OSBP)-related protein 3 (ORP3) is highly expressed in epithelial, neuronal and hematopoietic cells, as well as in certain forms of cancer. We assessed the function of ORP3 in HEK293 cells and in human macrophages. We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of β1 integrin activity–effects similar to those of constitutively active R-Ras(38V). Overexpression of ORP3 leads to formation of polarized cell-surface protrusions, impaired cell spreading and decreased β1 integrin activity. In primary macrophages, overexpression of ORP3 leads to the disappearance of podosomal structures and decreased phagocytotic uptake of latex beads, consistent with a role in actin regulation. ORP3 is phosphorylated when cells lose adhesive contacts, suggesting that it is subject to regulation by outside-in signals mediated by adhesion receptors. The present findings demonstrate a new function of ORP3 as part of the machinery that controls the actin cytoskeleton, cell polarity and cell adhesion.

Key words: Actin cytoskeleton, Cell adhesion, Cell polarization, Cell spreading, HEK293, Macrophages, Oxysterol-binding protein, R-Ras






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