PTEN Mutants Act as Dominant Negatives to Disrupt PTEN Activity

Loss of the tumor suppressor PTEN via genetic deletion or mutation impairs dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), facilitating activation of PI3K/AKT signaling that promotes tumor growth. Heterozygous missense mutations that inactivate PTEN catalytic activity have been associated with enhanced tumor formation compared with partial loss of PTEN expression, suggesting that mutant PTEN may negatively regulate wild-type PTEN function. Papa and colleagues found that PTEN proteins can form dimeric complexes, which were favored by dephosphorylation of the PTEN C-terminal tail and resulted in increased lipid phosphatase activity toward PIP3 compared with monomeric PTEN. Intriguingly, cancer-associated, catalytically inactive PTEN mutants formed heterodimers with wild-type PTEN protein at the plasma membrane and suppressed the phosphatase activity of wild-type PTEN toward PIP3, suggestive of a dominant negative function for mutant PTEN that may promote tumorigenesis. Consistent with this idea, heterozygous expression of PTEN^C124S or PTEN^G129E in knockin mouse models exacerbated lymphoid hyperplasia and augmented solid tumor formation compared with Pten^+/− mice, even in the absence of loss of heterozygosity. The ability of mutant PTEN to promote tumorigenesis was mediated by hyperactivation of AKT signaling in both murine cells and human tumor samples with heterozygous PTEN mutations, including glioblastoma and endometrial cancers. These results provide insights into the regulation of PTEN function and the mechanisms by which PTEN mutations accelerate tumor formation. Furthermore, these findings suggest that patients expressing inactivating missense mutations in PTEN may benefit from early treatment with AKT inhibitors.

Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 2014;157:595–610.