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.
journal_name
Celljournal_title
Cellauthors
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,Famulok Mdoi
10.1016/j.cell.2010.09.011subject
Has Abstractpub_date
2010-10-15 00:00:00pages
201-11issue
2eissn
0092-8674issn
1097-4172pii
S0092-8674(10)01059-7journal_volume
143pub_type
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