Article (Scientific journals)
K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness
Manoharan, Ganesh babu; LAURINI, Christina; BOTTONE, Sara et al.
2023In Cancers
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Keywords :
K-Ras; centrin; calmodulin
Abstract :
[en] Recent data suggest that K-Ras4B (hereafter K-Ras) can drive cancer cell stemness via calmodulin (CaM)-dependent, non-canonical Wnt-signalling. Here we examined whether another Ca2+-binding protein, the CaM-related centrin1, binds to K-Ras and could mediate some K-Ras functions that were previously ascribed to CaM. While CaM and centrin1 appear to distinguish between peptides that were derived from their classical targets, they both bind to K-Ras in cells. Cellular BRET- and immunoprecipitation data suggest that CaM engages more with K-Ras than centrin1 and that the interaction with the C-terminal membrane anchor of K-Ras is sufficient for this. Surprisingly, binding of neither K-Ras nor its membrane anchor alone to CaM or centrin1 is sensitive to inhibition of prenylation. In support of an involvement of the G-domain of K-Ras in cellular complexes with these Ca2+-binding proteins, we find that oncogenic K-RasG12V displays increased engagement with both CaM and centrin1. This is abrogated by addition of the D38A effector-site mutation, suggesting that K-RasG12V is held together with CaM or centrin1 in complexes with effectors. When treated with CaM inhibitors, the BRET-interaction of K-RasG12V with centrin1 was also disrupted in the low micromolar range, comparable to that with CaM. While CaM predominates in regulating functional membrane anchorage of K-Ras, it has a very similar co-distribution with centrin1 on mitotic organelles. Given these results, a significant overlap of the CaM- and centrin1-dependent functions of K-Ras is suggested.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Manoharan, Ganesh babu;  Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
LAURINI, Christina ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
BOTTONE, Sara ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
BEN FREDJ, Nesrine ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
ABANKWA, Daniel  ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
External co-authors :
no
Language :
English
Title :
K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness
Publication date :
2023
Journal title :
Cancers
eISSN :
2072-6694
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Basel, Switzerland
Peer reviewed :
Peer Reviewed verified by ORBi
FnR Project :
FNR13673303 - Investigation Of Nanoscale Ras Polarizations In Instructing Cancer Cell Stemness, 2019 (01/09/2020-31/08/2023) - Daniel Abankwa
Available on ORBilu :
since 06 August 2023

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