Discovery of new protein involved in regulating the second most commonly mutated tumor suppressor in human tumors

Scientists in Tokyo have discovered a new protein, named PICT-1, that is involved in regulating PTEN, the second most commonly mutated tumor suppressor in human tumors.

This discovery suggests the possibility of a new tumorigenic pathway that is due to defects in a protein involved in stabilizing PTEN rather than defects in PTEN itself.

The research appears as the "Paper of the Week" in the October 29 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Mutations in the PTEN tumor suppressor are found in a variety of human cancers including breast and prostate cancers. Approximately 20 percent of the mutations are located in a segment of 70 amino acids at the C-terminus of PTEN. These mutations lead to the rapid degradation of PTEN in cells, indicating that this region is critical for ensuring PTEN stability.

Studies have shown that cells add phosphate molecules to specific serine and threonine residues within the C-terminal segment to stabilize PTEN. Curious about the proteins involved in this stabilization, Dr. Tomohiko Maehama and his colleagues at the Tokyo Metropolitan Institute of Medical Science and the Tokyo Metropolitan University screened a library of human brain cDNA to find proteins that interact with PTEN. They identified a new protein that binds to the C-terminus of PTEN and named it PICT-1 (protein interacting with the carboxyl terminus 1).

Maehama and his colleagues discovered that PTEN molecules with mutations in their C-terminus are unable to bind to PICT-1, and that PICT-1 stabilizes PTEN by regulating the phosphorylation of a serine in the C-terminal segment. "From scientific point of view, it should be noted that PICT-1 is the first protein that interacts with the PTEN protein and regulates its phosphorylation," said Maehama.

The researchers hypothesize that PICT-1 may affect phosphorylation by activating a kinase or inhibiting a phosphatase. The identification of PTEN regulators has been a tremendously difficult problem and this research represents a huge breakthrough.

Maehama explained that this discovery indicates that cells with impaired PICT-1 function may become cancerous because of the resulting instability in PTEN. This would represent a new tumorigenic pathway that is not due to a defective PTEN gene but rather a loss of PTEN function caused by PICT-1. If this is the case, then this new type of tumor may be treated with rapamycin or related drugs that are often used in cancers resulting from PTEN loss of function.