Cytohesins are cytoplasmic ErbB receptor activators.
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.
Bill
Anke
A
LIMES Institute, Program Unit Chemical Biology & Medicinal Chemistry, Laboratory of Chemical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.
Schmitz
Anton
A
Albertoni
Barbara
B
Song
Jin-Na
JN
Heukamp
Lukas C
LC
Walrafen
David
D
Thorwirth
Franziska
F
Verveer
Peter J
PJ
Zimmer
Sebastian
S
Meffert
Lisa
L
Schreiber
Arne
A
Chatterjee
Sampurna
S
Thomas
Roman K
RK
Ullrich
Roland T
RT
Lang
Thorsten
T
Famulok
Michael
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D019281:Dimerization; D066246:ErbB Receptors / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology
D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C516025:SecinH3; D014230:Triazoles; C100723:cytohesin-1; C102474:cytohesin-2; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases