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UBTD1 is a mechano-regulator controlling cancer aggressiveness

Artikel i vetenskaplig tidskrift
Författare S. Torrino
F. R. Roustan
L. Kaminski
T. Bertero
S. Pisano
D. Ambrosetti
M. Dufies
Jay Uhler
E. Lemichez
A. Mettouchi
M. Gesson
K. Laurent
C. Gaggioli
J. F. Michiels
C. Lamaze
F. Bost
S. Clavel
Publicerad i Embo Reports
Volym 20
Nummer/häfte 4
ISSN 1469-221X
Publiceringsår 2019
Publicerad vid Institutionen för biomedicin
Språk en
Länkar dx.doi.org/10.15252/embr.201846570
Ämnesord matrix stiffness, ROCK2, UBTD1, YAP, beta-TrCP, cell-cell adhesion, hippo pathway, size-control, yap/taz, yap, growth, stiffness, proteins
Ämneskategorier Cancer och onkologi, Cell- och molekylärbiologi

Sammanfattning

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with beta-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase beta-TrCP. Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

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