Protein phosphatase 2A (PP2A) is a serine–threonine phosphatase complex that contains three subunits. William C. Hahn and colleagues have found that mutations in the PP2A-Aα subunit contribute to human tumorigenesis by inducing functional haploinsufficiency.

The catalytic (C), regulatory (B) and structural (A) subunits of PP2A all have several isoforms. The mutant forms of the Aα-subunit that are found in human tumours are known to disrupt binding to the other subunits.

The authors tested the hypothesis that these mutant Aα-subunits exert a dominant effect by introducing them into a human cell line. Although the mutants disrupted the formation of the PP2A complex, which in turn reduced phosphatase activity, there was no increase in proliferation and no anchorage-independent growth or tumour formation.

The alternative hypothesis is that the non-functionality of these mutants causes tumorigenesis by reducing the levels of functional PP2A (haploinsufficiency). The authors used short hairpin RNAs (shRNAs) to reduce the expression of PP2A-Aα in the same cell line. They reduced expression by different amounts by increasing the titre of the shRNA. They found that reducing the amount of PP2A-Aα to approximately half of that found in wild-type cells caused an increase in proliferation, anchorage-independent growth and, when the cells were transplanted into immunodeficient mice, tumorigenesis. Interestingly, however, when the levels of PP2A-Aα were reduced further, the cells became apoptotic rather than proliferative.

In all cases in which the levels of PP2A-Aα were reduced, a decrease in the levels of the B-subunit and the C-subunit was also found, indicating that these are unstable when not bound to the A-subunit. Also, a reduction in Aα-subunits would make the B-subunit and C-subunit compete for A-subunits, with a consequent reduction in the number of certain types of complex. In particular, complexes that contained the B56γ-subunit were undetectable. Suppressing this subunit had previously been shown by the same authors to cause transformation.

Therefore, these findings add another link to our understanding of transformation and provide more evidence for the significance of haploinsufficiency as a mechanism in tumorigenesis.