Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor.
The PTEN (phosphatase and tensin homologue) tumor suppressor protein contains a single catalytic domain with both lipid and protein phosphatase activities. The remaining C-terminal half of the PTEN protein plays a role in its stability and is mutated in many clinical cancer samples. Here, we report that the PTEN C-terminal domain physically interacts with the forkhead-associated domain of the oncogenic MSP58 protein and that this interaction requires PTEN Thr-366. We further show that while MSP58 transforms Pten-/- mouse embryo fibroblasts (MEFs), concurrent introduction of wild-type PTEN causes a dramatic reduction in the number of MSP58-induced transformed foci. This PTEN-mediated inhibition of cellular transformation requires physical interaction as evidenced by the failure of PTEN(T366A) point mutation (residing within the MSP58 interaction domain) to suppress MSP-58-driven transformation. These observations, together with the capacity of catalytically inactive PTEN mutant (G129R) to suppress MSP58 oncogenicity, support the view that the C-terminal region of PTEN directly provides a previously uncharacterized biological function in its ability to regulate cellular transformation.
Okumura
Koichi
K
Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, CA 92093-0660, USA.
Zhao
Mujun
M
Depinho
Ronald A
RA
Furnari
Frank B
FB
Cavenee
Webster K
WK
D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D009857:Oncogenes; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000502:physiology*; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology*
C113292:MCRS1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human