Abstract
Backgroundp120-catenin (p120) is the prototypical member of a subclass of armadillo-related proteins that includes δ-catenin/NPRAP, ARVCF, p0071, and the more distantly related plakophilins 1–3. In vertebrates, p120 is essential in regulating surface expression and stability of all classical cadherins, and directly interacts with Kaiso, a BTB/ZF family transcription factor.Methodology/Principal FindingsTo clarify functional relationships between these proteins and how they relate to the classical cadherins, we have examined the proteomes of 14 diverse vertebrate and metazoan species. The data reveal a single ancient δ-catenin-like p120 family member present in the earliest metazoans and conserved throughout metazoan evolution. This single p120 family protein is present in all protostomes, and in certain early-branching chordate lineages. Phylogenetic analyses suggest that gene duplication and functional diversification into “p120-like” and “δ-catenin-like” proteins occurred in the urochordate-vertebrate ancestor. Additional gene duplications during early vertebrate evolution gave rise to the seven vertebrate p120 family members. Kaiso family members (i.e., Kaiso, ZBTB38 and ZBTB4) are found only in vertebrates, their origin following that of the p120-like gene lineage and coinciding with the evolution of vertebrate-specific mechanisms of epigenetic gene regulation by CpG island methylation.Conclusions/SignificanceThe p120 protein family evolved from a common δ-catenin-like ancestor present in all metazoans. Through several rounds of gene duplication and diversification, however, p120 evolved in vertebrates into an essential, ubiquitously expressed protein, whereas loss of the more selectively expressed δ-catenin, p0071 and ARVCF are tolerated in most species. Together with phylogenetic studies of the vertebrate cadherins, our data suggest that the p120-like and δ-catenin-like genes co-evolved separately with non-neural (E- and P-cadherin) and neural (N- and R-cadherin) cadherin lineages, respectively. The expansion of p120 relative to δ-catenin during vertebrate evolution may reflect the pivotal and largely disproportionate role of the non-neural cadherins with respect to evolution of the wide range of somatic morphology present in vertebrates today.
Highlights
The integration over time of increasingly sophisticated signaling and cell-cell adhesion mechanisms has likely been an essential and ongoing process in the evolution of complex metazoan life
Fly p120/d-catenin associates and colocalizes with fly E-cadherin [16], the evidence overall suggests that its role is not directly comparable to that of vertebrate p120
The phylogenetic analyses presented here show that they evolved through rounds of gene duplication and functional diversification from an ancient ‘‘d-catenin-like’’ gene that is conserved throughout metazoan evolution
Summary
The integration over time of increasingly sophisticated signaling and cell-cell adhesion mechanisms has likely been an essential and ongoing process in the evolution of complex metazoan life. In vertebrates, p120 has evolved one or more essential functions relative to its invertebrate counterpart, and a critical role with respect to the classical cadherins. We have analyzed proteomes from 14 diverse metazoan species to understand the evolution of the p120 protein family and the origin of its functional association with classical cadherins and Kaiso. We find that all invertebrates as well as several earlybranching chordate lineages contain a single family member with a ‘‘d-catenin-like’’ set of functions, suggesting that the p120family ancestor was ‘‘d-catenin-like’’ and highly conserved in prevertebrate metazoans. The vertebrate specific appearance of Kaiso and its unique interactions with p120, TCF4 and methylCpG DNA suggest other p120 connections relevant to Wnt signaling and vertebrate-specific mechanisms of transcriptional regulation
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