Figure 1.

Model of PP2A holoenzyme; location of human cancer-associated Aα mutations; high frequency of Aα mutations in endometrial cancer. (B) Trimeric PP2A holoenzyme consists of one catalytic subunit (Cα or Cβ), one scaffolding subunit (Aα or Aβ) and one of several regulatory subunits (B, B' or B”). Aα and Aβ consist of 15 repeats connected by inter-repeat loops. Each repeat consists of two antiparallel α-helices connected by intra-repeat loops. (A) Aα mutations in endometrial (endo) or ovarian (ovary) cancer are clustered at or near intra-repeat loop 5 of repeat 5 (from P179 to R183) and at or near intra-repeat loop 7 of repeat 7 (from R249 to R258). Numbers in parentheses represent number of tumors with a mutation at a particular site.⁶–⁹ E64D, E64G and R418W were found in lung, breast and skin cancer, respectively.¹⁰ Shown in (C and D) are C-terminal truncations, Δ171–589 from breast cancer missing repeats 6 to 15¹⁰ and Δ375–589 from kidney cancer missing repeats 11 to 15.¹¹ (E) Frequency of Aα mutations in endometrial (18%, 31/171) and ovarian (6%, 27/470) cancers in comparison to K-ras, Arf, p53 and PI3K.⁶–⁹ (F) Loss of Bα, B'γ3 (formerly known as B'α1),¹² and B”/PR72 binding to mutant Aα. Note: All Aα mutants are defective in B'γ3 binding.¹³,¹⁴ For E393Q, see reference ¹⁵; for R183W in pancreatic (pa) cancer, see reference ¹⁶; *indicates synthetic mutant.