Evolutionary Analysis of the B56 Gene Family of PP2A Regulatory Subunits

Abstract

Protein phosphatase 2A (PP2A) is an abundant serine/threonine phosphatase that functions as a tumor suppressor in numerous cell-cell signaling pathways, including Wnt, myc, and ras. The B56 subunit of PP2A regulates its activity, and is encoded by five genes in humans. B56 proteins share a central core domain, but have divergent amino- and carboxy-termini, which are thought to provide isoform specificity. We performed phylogenetic analyses to better understand the evolution of the B56 gene family. We found that B56 was present as a single gene in eukaryotes prior to the divergence of animals, fungi, protists, and plants, and that B56 gene duplication prior to the divergence of protostomes and deuterostomes led to the origin of two B56 subfamilies, B56αβε and B56γδ. Further duplications led to three B56αβε genes and two B56γδ in vertebrates. Several nonvertebrate B56 gene names are based on distinct vertebrate isoform names, and would best be renamed. B56 subfamily genes lack significant divergence within primitive chordates, but each became distinct in complex vertebrates. Two vertebrate lineages have undergone B56 gene loss, Xenopus and Aves. In Xenopus, B56δ function may be compensated for by an alternatively spliced transcript, B56δ/γ, encoding a B56δ-like amino-terminal region and a B56γ core.

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

“…Plant B56 subunit clades are distinct and separate from those formed by animal B56 isoforms, indicating independent expansion of plant and animal B56 gene families (Fig. 1), consistent with the results of previous analyses (Terol et al, 2002;Sommer et al, 2015); thus, plant and animal B56 isoforms exhibit no orthologous relationships. The flowering plant B56 family groups into five clades: one containing Arabidopsis isoforms B3, B4, and B7 (B3/4/7), one containing B5 and B8 (B5/8), one containing B6, B9, and B10 (B6/9/10), one containing B11, and a final clade missing from Arabidopsis and other Brassicaceae, which we have designated as B∅ ( Fig.…”

“…S4 and S5). Consistent with previous analyses (Sommer et al, 2015), the five human B56 isoforms B9a, B9b, B9g, B9d, and B9« represent vertebrate-specific lineages that originated prior to the split of cartilaginous and bony fish ( Fig. 1; Supplemental Figs.…”

“…Among vertebrate B56 isoforms, we detected statistically significant positive selection at the base of the B9g/d clade, at the base of the B9a/b/« clade, and on the B9a branch (Table IV). Interestingly, no positive selection was detected for B9b, which appears to have been lost in birds (Sommer et al, 2015). Our analysis also revealed positive selection in the plant B56 family.…”

“…Within the vertebrate B9a/b/« clade, we detected positive selection only on B9a, suggesting that B9b and B9« may be functionally overlapping. Functional overlap of B9b and B9« (or B9a) has been proposed previously as an explanation for the reported loss of B9b in birds (Sommer et al, 2015). Among B56 lineages leading to Arabidopsis isoforms, the strongest evidence for positive selection was in the B11 and B3/4/7 clades.…”

“…B9b in birds; Sommer et al, 2015). However, plants exhibit numerous examples of lineage-specific isoform losses that occur in all five PP2A gene families (Table II).…”