The tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10) dephosphorylates phosphatidylinositol-3, 4, 5-trisphosphate (PIP3), thereby inhibiting activation of the oncogenic kinase AKT. Cancers from diverse tissues have reduced PTEN activity conferred by various mechanisms, such as missense or truncation mutations in PTEN (see Leslie and Hertog). Papa et al. found that mutant PTEN can dimerize with wild-type PTEN and suppress its activity. Biochemical approaches in vitro and in cultured cells using both overexpressed and endogenous proteins showed that PTEN homodimerizes using multiple interfaces and is catalytically active in its dimeric form. Mutation of phosphorylated residues in the C terminus of PTEN and analysis by gel filtration suggested that phosphorylation of PTEN inhibits its dimerization, consistent with the observation that PTEN activity is inhibited by phosphorylation. Forms of PTEN with the cancer-associated mutations C124S and G129E, which inhibit its lipid phosphatase activity, also homodimerized and heterodimerized with endogenous wild-type PTEN. In vitro dephosphorylation assays indicated that homodimeric wild-type PTEN was more active than PTEN-PTENC124S or PTEN-PTENG129E heterodimers. Mice heterozygous for PtenC124S (PtenC124S/+) or PtenG129E (PtenG129E/+) had accelerated the onset of hyperproliferation of lymphocytes and extramedullary hematopoiesis, and more of these mice had adrenal, thyroid, and gall bladder adenomas than mice with heterozygous knockout of Pten (Pten+/–). PtenC124S/+ mice developed lung adenomas, PtenG129E/+ mice developed liver adenomas, and both mutant mice developed large invasive mammary adenocarcinomas; none of these tumors were detected in Pten+/– mice. The amount of PIP3 and the phosphorylation of AKT and its downstream targets was greater in primary mouse embryonic fibroblasts stimulated with insulin or insulin-like growth factor and mammary epithelial cells from PtenC124S/+or PtenG129E/+ mice compared with those from Pten+/– mice. Unlike Pten+/– mice, the tumors of PtenC124S/+and PtenG129E/+ mice did not show loss of heterozygosity for the wild-type Pten allele. In human cancers, phosphorylation of AKT was increased in patients with heterozygous mutation of PTEN compared to those with heterozygous loss of PTEN. Thus, single-allele mutation of PTEN is more oncogenic than comparable loss of PTEN owing to the inhibition of protein encoded by the wild-type PTEN allele.
A. Papa, L. Wan, M. Bonora, L. Salmena, M. S. Song, R. M. Hobbs, A. Lunardi, K. Webster, C. Ng, R. H. Newton, N. Knoblauch, J. Guarnerio, K. Ito, L. A. Turka, A. H. Beck, P. Pinton, R. T. Bronson, W. Wei, P. P. Pandolfi, Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 157, 595–610 (2014). [PubMed]
N. R. Leslie, J. den Hertog, Mutant PTEN in cancer: Worse than nothing. Cell 157, 527–529 (2014). [PubMed]