Protein phosphatase 2A A{alpha} regulates A{beta} protein expression and stability [Cell Biology] (Journal of Biological Chemistry)

Protein phosphatase 2A (PP2A) represses many oncogenic signaling pathways and is an important tumor suppressor. PP2A comprises three distinct subunits and forms through a highly regulated biogenesis process, with the scaffolding A subunit existing as two highly related isoforms, A? and A?. PP2A`s tumor-suppressive functions have been intensely studied, and PP2A inactivation has been shown to be a prerequisite for tumor formation. Interestingly, although partial loss of the A? isoform is growth promoting, complete A? loss has no transformative properties. Additionally, in cancer patients, A? is found to be inactivated in a haploinsufficient manner. Using both cellular and in vivo systems, colorectal and endometrial cancer cell lines, and biochemical and cellular assays, here we examined why the complete loss of A? does not promote tumorigenesis. CRISPR/Cas9-mediated homozygous A? deletion resulted in decreased colony formation and tumor growth across multiple cell lines. Protein expression analysis of PP2A family members revealed that the A? deletion markedly up-regulates A? protein expression by increasing A? protein stability. A? knockdown in control and A? knockout cell lines indicated that A? is necessary for cell survival in the A? knockout cells. In the setting of A? deficiency, co-immunoprecipitation analysis revealed increased binding of specific PP2A regulatory subunits to A?, and knockdown of these regulatory subunits restored colony-forming ability. Taken together, our results uncover a mechanism by which PP2A A? regulates A? protein stability and activity and suggests why homozygous loss of A? is rarely seen in cancer patients.