UBTD1 is a mechano‐regulator controlling cancer aggressiveness

Abstract

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 β‐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 β‐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.

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling

“…This critical switch is controlled by EGFR ubiquitination [33,34]. We and others showed by antibody-based and antibody-free methods that UBTD1 is localized in various cell compartments including the plasma membrane, ER and vesicles [14,35]. Therefore, we first speculated that UBTD1 was implicated in EGFR cargoes internalization through ubiquitination of the receptor.…”

“…Recently, we have shown that UBTD1 controls the degradation of the transcriptional regulator YAP (yesassociated protein) by modulating its ubiquitination [14]. Mechanistically, UBTD1 is a component of the ubiquitination complex that allows the E3 ligase β-TRCP (beta-transducin repeats-containing proteins) to interact with YAP.…”

“…In this hierarchical framework, there are only two E1s, over 30 E2s and hundreds of E3s in human, illustrating the large spectrum of E2s that contrasts with the high specificity of E3s in the recognition of substrates [10,11]. While the interaction of E3s with their substrates confers specificity to the system, E2s are more versatile and are commonly considered as "ubiquitin carriers" with an auxiliary rather than control role.However, the modulation of the functionality of E2/E3 complexes by scaffold proteins has been poorly investigated and few proteins acting on these complexes have been characterized [11,12].Ubiquitin domain-containing protein 1 (UBTD1) is an evolutionarily-conserved protein which interacts, both in vitro and in vivo, with some E2 and E3 enzymes of the ubiquitin-proteasome system (UPS) [13].Recently, we have shown that UBTD1 controls the degradation of the transcriptional regulator YAP (yesassociated protein) by modulating its ubiquitination [14]. Mechanistically, UBTD1 is a component of the ubiquitination complex that allows the E3 ligase β-TRCP (beta-transducin repeats-containing proteins) to interact with YAP.…”

“…2), the E3 enzyme that degrades p53 [15]. Importantly, a decreased expression of UBTD1 is associated with increased cancer aggressiveness and decreased overall patient survival in colorectal, liver, prostate, and lung cancer [13,14,16]. Based on these evidences, we have previously suggested that UBTD1 may be an E2/E3 scaffolding protein acting as a tumor suppressor [14].…”

Mechanical Cues Affect Migration and Invasion of Cells From Three Different Directions

“…Apart from actin filament polymerization based protrusive forces, it has been hypothesized that the suppression of myosin contractility has an impact on the directionality of cell movement (Puleo et al, 2019). There is an upregulation of genes/proteins such as Ubiquitin domain−containing protein 1 (UBTD 1) that interact with E2 enzymes of the ubiquitin-proteasome system due to environmental cues, such as stiff matrices (Torrino et al, 2019). Rather unexpected is the fact that suppression of myosin activity had no impact on mechanically guided directed motility.…”