PMID:20946980

Citation	Bill, A, Schmitz, A, Albertoni, B, Song, JN, Heukamp, LC, Walrafen, D, Thorwirth, F, Verveer, PJ, Zimmer, S, Meffert, L, Schreiber, A, Chatterjee, S, Thomas, RK, Ullrich, RT, Lang, T and Famulok, M (2010) Cytohesins are cytoplasmic ErbB receptor activators. Cell 143:201-11
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.
Links	PubMed Online version:10.1016/j.cell.2010.09.011
Keywords	Adenocarcinoma/metabolism; Adenocarcinoma/pathology; Animals; Dimerization; GTPase-Activating Proteins/antagonists & inhibitors; GTPase-Activating Proteins/genetics; GTPase-Activating Proteins/metabolism; Gene Knockdown Techniques; Guanine Nucleotide Exchange Factors/antagonists & inhibitors; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; Humans; Lung Neoplasms/metabolism; Lung Neoplasms/pathology; Mice; Neoplasm Transplantation; Protein Structure, Tertiary; Receptor Protein-Tyrosine Kinases/metabolism; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction; Transplantation, Heterologous; Triazoles/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:EGFR_original		GO:0042802: identical protein binding	IPI: Inferred from Physical Interaction: UniProtKB:P00533	F
HUMAN:EGFR_original		GO:0005515: protein binding	IPI: Inferred from Physical Interaction: UniProtKB:Q9UJM3	F
HUMAN:EGFR_original		GO:0005515: protein binding	IPI: Inferred from Physical Interaction: UniProtKB:Q99418	F

References

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