The TGFβ signalling pathway controls plethora of cellular functions during embryogenesis and in adult tissues. Consequently abnormal TGFβ signalling is associated with multiple human diseases such as fibrosis, immune disorders and cancer. TGFβ signalling is initiated upon ligand binding to a pair of receptor serine/threonine protein kinases on the cell surface. This triggers the phosphorylation of SMAD2/3 leading to the assembly and nuclear translocation of active SMAD2/3/4 transcriptional complex, which, together with other co-factors, drives the transcription of hundreds of target genes. The activity of SMAD transcription factors is tightly regulated. Reversible ubiquitylation of active SMAD complexes serves to fine-tune the cellular responses to TGFβ signals. While much is known about the E3 ubiquitin ligases that modulate the ubiquitylation of SMADs, the deubiquitylating enzymes that act on active SMAD complexes, which drive the TGFβ signalling, remain undefined.
Lina’s work at the Medical Research Council - Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) in the past two years has uncovered a unique role for the deubiquitylating enzyme OTUB1 in regulating the active SMAD complexes and thereby the TGFβ pathway.
The key novel findings that Lina’s research has made are highlighted below:
- OTUB1 is recruited to the active phospho-SMAD2/3-SMAD4 complex only upon TGFβ-induction.
- TGFβ-induced phosphorylation of SMAD2/3 is necessary and sufficient for their interaction with OTUB1.
- OTUB1 enhances TGFβ-induced gene transcription and cellular migration.
- OTUB1 promotes TGFβ signalling by binding to phospho-SMAD2/3 and preventing their ubiquitylation and degradation through the inhibition of E2 ubiquitin conjugating enzymes.
Lina’s findings uncover for the first time a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGFβ pathway. OTUB1 is the only DUB shown thus far to act on active SMAD2/3, while the deubiquitylase activity of OTUB1 appears not to be necessary. More recent studies have also reported such non-canonical mode of action for OTUB1 in the control of chromatin stability and DNA-damage responses. Lina’s findings are not only significant within the TGFβ pathway, but may advance the field of deubiquitylation, especially when taking into account stimuli-induced phospho-dependent recruitment of a DUB to its target.
Mazin Al-Salihi, Thomas Macartney and Simone Weidlich also contributed to this research.
The paper entitled “OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3” can be accessed through Nature Communications.
Lina Herhaus, Mazin Al-Salihi, Thomas Macartney, Simone Weidlich & Gopal P. Sapkota (2013). “OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3.” Nature Communications, 4:2519 | DOI: 10.1038/ncomms3519