Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation.
Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Maja
M
Šolman
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Alessio
A
Ligabue
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Olga
O
Blaževitš
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Alok
A
Jaiswal
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States.
Yong
Y
Zhou
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States.
Hong
H
Liang
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Benoit
B
Lectez
Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.
Kari
K
Kopra
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Camilo
C
Guzmán
Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.
Harri
H
Härmä
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States.
John F
JF
Hancock
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Tero
T
Aittokallio
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
Daniel
D
Abankwa
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000473:pathology*; D055503:Protein Multimerization; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D018631:ras Proteins
Ras; biophysics; cancer; cell biology; human; membrane; nanoclustering; signalling; structural biology