Abstract
Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de-ubiquitinase OTUB1 as a negative regulator of RAS mono- and di-ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild-type RAS cells. An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development.
Highlights
The RAS small GTPases (HRAS, NRAS, and KRAS) are essential regulators of diverse eukaryotic cellular processes, such as cell proliferation, cytoskeletal assembly and organization, and intracellular membrane trafficking [for review (Colicelli, 2004)]
OTUB1 has been reported to regulate T-cell anergy by enhancing the degradation of the E3 ligase GRAIL (Lin et al, 2009), to augment TGF-b signaling by inhibiting degradation of phosphorylated SMAD2/3 (Herhaus et al, 2013), and to suppress DNA-damage-dependent chromatin ubiquitination (Nakada et al, 2010) and MDM2-mediated ubiquitination of the tumor suppressor p53 (Sun et al, 2012)
We found that OTUB1 promotes tumorigenic transformation of wt RAS cells by triggering the RAS/ MAPK pathway
Summary
The RAS small GTPases (HRAS, NRAS, and KRAS) are essential regulators of diverse eukaryotic cellular processes, such as cell proliferation, cytoskeletal assembly and organization, and intracellular membrane trafficking [for review (Colicelli, 2004)]. The RAS family members function as molecular switches alternating between an inactive GDP-bound and active GTP-bound state. GDP- and GTP-bound forms is tightly regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Oncogenic RAS mutations occur in up to 30% of non-small-cell lung carcinomas (NSCLC), mostly adenocarcinomas (Karnoub & Weinberg, 2008). KRAS-mutant lung adenocarcinomas have higher levels of the MAPK pathway activation than wild-type (wt) KRAS tumors. The MAPK cascade is hyperactivated in a significant proportion of wt KRAS tumors, suggesting that RAS proteins may be frequently activated by alternative mechanisms not yet fully elucidated (Network, 2014)
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