Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

Blazevits, Olga, Mideksa, Yonatan G., Solman, Maja, Ligabue, Alessio, Ariotti, Nicholas, Nakhaeizadeh, Hossein, Fansa, Eyad K., Papageorgiou, Anastassios C., Wittinghofer, Alfred, Ahmadian, Mohammad R. and Abankwa, Daniel (2016) Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering. Scientific Reports, 6 . doi:10.1038/srep24165

Author Blazevits, Olga
Mideksa, Yonatan G.
Solman, Maja
Ligabue, Alessio
Ariotti, Nicholas
Nakhaeizadeh, Hossein
Fansa, Eyad K.
Papageorgiou, Anastassios C.
Wittinghofer, Alfred
Ahmadian, Mohammad R.
Abankwa, Daniel
Title Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-04-18
Year available 2016
Sub-type Article (original research)
DOI 10.1038/srep24165
Open Access Status DOI
Volume 6
Total pages 16
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
Abstract Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling.
Keyword Galectin-1 (Gal-1) dimers
H-ras nanoclustering
Ras binding domain (RBD)
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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