Protein promise for cancer
doi:10.1038/nindia.2011.65 Published online 4 May 2011
Cell biologists have identified a new protein that plays a crucial part in regulating the action of a well known tumor suppressor gene. Identification of the new protein makes it a novel potential target for drug development in future cancer therapies.
The protein – WWP2 – is technically an E3 ligase and has been identified as a novel regulator for the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10). PTEN has been an important gene to study since it controls cell proliferation and survival in cancers. When PTEN is mutated or lost, it could trigger the onset of tumors in many human cancers such as breast, prostate, lung, brain and colon.
Researchers have been trying to understand the molecular mechanisms of PTEN and the players involved in its regulation to design novel cancer therapeutics. Subba Reddy Maddika and his co-researchers at the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad have demonstrated in mouse models that WWP2 acts as a potential oncogene by degrading the important tumor suppressor PTEN.
WWP2 controls the stability of various proteins in a cell via the process of ubiquitination. Ubiquitination is known to regulate protein stability (through proteasomal degradation), thus maintaining cellular protein homeostasis and is also known to be involved in other functions like protein localization, transcription, cellular signaling and DNA damage response. "We found that WWP2 polyubiquitinates PTEN and leads to its degradation via proteasome," Maddika told Nature India.
The team also showed that WWP2 degraded PTEN through phosphorylation at a particular position in the gene – the tyrosine 155 residue. Interestingly, mutation in PTEN at Tyrosine 155 residue has been reported in many human cancer patients.
"Under normal conditions PTEN is phosphorylated at tyrosine 155 residue which prevents the association of WWP2 with it. But under cancerous conditions PTEN is mutated at tyrosine 155 which no longer is phosphorylated and thus enables WWP2 to act as an oncogene by degrading PTEN," Maddika explained.
- Maddika, S. et al. WWP2 is an E3 ubiquitin ligase for PTEN. Nat. Cell. Biol. doi: 10.1038/ncb2240 (2011) 10.1038/ncb2240