RT Journal Article
SR Electronic
T1 Competitive Inhibitors of Ras Effector Binding
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 548750
DO 10.1101/548750
A1 Svenja Wiechmann
A1 Pierre Maisonneuve
A1 Britta M. Grebbin
A1 Meike Hoffmeister
A1 Manuel Kaulich
A1 Hans Clevers
A1 Krishnaraj Rajalingam
A1 Igor Kurinov
A1 Henner F. Farin
A1 Frank Sicheri
A1 Andreas Ernst
YR 2019
UL http://biorxiv.org/content/early/2019/02/26/548750.abstract
AB The small GTPases H, K and NRas are molecular switches that are indispensable for the correct regulation of cellular proliferation and growth. Mutations in Ras are associated with cancer and result in unwanted activation of signaling processes caused by aberrant recruitment of downstream effector proteins. In this study, we have engineered variants of the Ras-binding domain (RBD) of CRAF kinase that bind with highly improved affinity the effector binding site of Ras. Structural characterization demonstrates how the engineered RBD variants outcompete effector binding and inhibit Ras signaling in cells leading to apoptosis, growth arrest and senescence. The optimized RBD variants provide new insights in Ras biology and enabled the functional stratification of Ras dependency in patient-derived colorectal cancer organoids.One sentence summary Inhibition of effector kinase binding to Ras induces senescence in non-tumorigenic cells and reveals Ras dependency in patient-derived cancer organoids.