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  Cytohesins are cytoplasmic ErbB receptor activators

Bill, A., Schmitz, A., Albertoni, B., Song, J. N., Heukamp, L. C., Walrafen, D., et al. (2010). Cytohesins are cytoplasmic ErbB receptor activators. Cell, 143(2), 201-11. doi:10.1016/j.cell.2010.09.011.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-643B-E Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-643C-C
Genre: Journal Article

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Bill, A., Author
Schmitz, A., Author
Albertoni, B., Author
Song, J. N., Author
Heukamp, L. C., Author
Walrafen, D., Author
Thorwirth, F., Author
Verveer, P. J., Author
Zimmer, S., Author
Meffert, L., Author
Schreiber, A., Author
Chatterjee, S., Author
Thomas, R. K., Author
Ullrich, R. T., Author
Lang, T., Author
Famulok, M.1, Author
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1External Organizations, ou_persistent22              

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Free keywords: Adenocarcinoma/metabolism/*pathology Animals Dimerization GTPase-Activating Proteins/antagonists & inhibitors/genetics/metabolism Gene Knockdown Techniques Guanine Nucleotide Exchange Factors/antagonists & inhibitors/genetics/*metabolism Humans Lung Neoplasms/metabolism/*pathology Mice Neoplasm Transplantation Protein Structure, Tertiary Receptor Protein-Tyrosine Kinases/*metabolism Receptor, Epidermal Growth Factor/*metabolism Signal Transduction Transplantation, Heterologous Triazoles/pharmacology
 Abstract: Signaling by ErbB receptors requires the activation of their cytoplasmic kinase domains, which is initiated by ligand binding to the receptor ectodomains. Cytoplasmic factors contributing to the activation are unknown. Here we identify members of the cytohesin protein family as such factors. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, whereas cytohesin overexpression stimulated receptor activation. Monitoring epidermal growth factor receptor (EGFR) conformation by anisotropy microscopy together with cell-free reconstitution of cytohesin-dependent receptor autophosphorylation indicate that cytohesins facilitate conformational rearrangements in the intracellular domains of dimerized receptors. Consistent with cytohesins playing a prominent role in ErbB receptor signaling, we found that cytohesin overexpression correlated with EGF signaling pathway activation in human lung adenocarcinomas. Chemical inhibition of cytohesins resulted in reduced proliferation of EGFR-dependent lung cancer cells in vitro and in vivo. Our results establish cytohesins as cytoplasmic conformational activators of ErbB receptors that are of pathophysiological relevance.

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 Dates: 2010
 Publication Status: Issued
 Pages: -
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 Identifiers: Other: 20946980
DOI: 10.1016/j.cell.2010.09.011
ISSN: 1097-4172 (Electronic)
ISSN: 0092-8674 (Linking)
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Title: Cell
  Alternative Title : Cell
Source Genre: Journal
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Pages: - Volume / Issue: 143 (2) Sequence Number: - Start / End Page: 201 - 11 Identifier: -