PTEN prevents tumor cells from growing uncontrollably, and mutations
in the gene encoding this protein are commonly found in many different
types of cancer.
Researchers at Cold Spring Harbor Laboratory in New York have
discovered that a protein called Importin-11 protects the anti-cancer
protein PTEN from destruction by transporting it into the cell nucleus.
‘A protein called Importin-11 protects the anti-cancer protein PTEN from destruction by transporting it into the cell nucleus.’
The study, "The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein," which will be published online February 13 in The Journal of Cell Biology
, suggests that the loss of Importin-11 may destabilize PTEN, leading to the development of lung, prostate, and other cancers.
Some patients, however, show low levels of the PTEN
protein even though their PTEN genes are normal. Lloyd Trotman, Muhan
Chen, Dawid Nowak, and colleagues discovered that this may be due to
defects in a protein called Importin-11 that transports PTEN into the
nucleus, sheltering PTEN from cytoplasmic proteins that would otherwise
target it for degradation.
Several cytoplasmic proteins - NEDD4-1, NDFIP1, and UBE2E1 - combine
to tag PTEN with the small molecule ubiquitin. PTEN tagged with multiple
ubiquitin molecules can then be recognized and destroyed by the cell's
protein degradation machinery. Trotman and colleagues found that
Importin-11 protects PTEN from degradation by escorting not only PTEN
but also UBE2E1 into the nucleus, thereby breaking up the cytoplasmic
Mice lacking Importin-11 showed lower levels of PTEN protein and
developed lung adenocarcinomas and prostate neoplasias. Mutations in the
gene encoding Importin-11 have been identified in human cancers, and
Trotman and colleagues found that tumors from lung cancer patients
lacking Importin-11 tended to show low PTEN levels as well. The
researchers estimate that loss of Importin-11 may account for the loss
of PTEN in approximately one third of lung cancer patients lacking this
key anti-cancer protein.
In prostate cancer, loss of Importin-11 predicted disease relapse
and metastasis in patients who had had their prostates removed. "We
think that the degradation of PTEN after loss or impairment of
Importin-11 is a very effective driver of human prostate cancer," says
Trotman. "Our results suggest that Importin-11 is the "Achilles' heel"
of the ubiquitination system that maintains the correct levels of PTEN