The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor.

Javier U Chicote,Rob Desalle,Antonio García-España,Tung-Tien Sun,José Segarra

doi:10.1371/journal.pone.0170196

Abstract

Uroplakins are a widespread group of vertebrate integral membrane proteins that belong to two different families: UPK1a and UPK1b belong to the large tetraspanin (TSPAN) gene family, and UPK3a, UPK3b, UPK3c, UPK3d, UPK2a and UPK2b form a family of their own, the UPK2/3 tetraspanin-associated family. In a previous study, we reported that uroplakins first appeared in vertebrates, and that uroplakin tetraspanins (UPK1a and UPK1b) should have originated by duplication of an ancestor tetraspanin gene. However, the evolutionary origin of the UPK2/3 family remains unclear. In this study, we provide evidence that the UPK2/3 family originated by gene duplication and domain loss from a protoPTPRQ-like basal deuterostome gene. PTPRQs are members of the subtype R3 tyrosine phosphatase receptor (R3 PTPR) family, which are characterized by having a unique modular composition of extracellular fibronectin (FN3) repeats, a transmembrane helix, and a single intra-cytoplasmic phosphotyrosine phophatase (PTP) domain. Our assumption of a deuterostome protoPTPRQ-like gene as an ancestor of the UPK2/3 family by gene duplication and loss of its PTP and fibronectin (FN3) domains, excluding the one closest to the transmembrane helix, is based on the following: (i) phylogenetic analyses, (ii) the existence of an identical intron/exon gene pattern between UPK2/3 and the corresponding genetic region in R3 PTPRs, (iii) the conservation of cysteine patterns and protein motifs between UPK2/3 and PTPRQ proteins and, (iv) the existence in tunicates, the closest organisms to vertebrates, of two sequences related to PTPRQ; one with the full subtype R3 modular characteristic and another without the PTP domain but with a short cytoplasmic tail with some sequence similarity to that of UPK3a. This finding will facilitate further studies on the structure and function of these important proteins with implications in human diseases.

Highlights

Uroplakins (UPKs) are integral membrane proteins belonging to two families: UPK1a (UPIa) and UPK1b (UPIb) are members of the four-transmembrane domain tetraspanin (TSPAN or TM4SF) family [1,2]; and the single-spanning transmembrane uroplakins UPK2a, UPK2b, UPK3a (UPIIIa, UPK3A), UPK3b (UPIIIb, UPK3B), UPK3c (UPK3BL; present in mammals, reptiles and birds) and UPK3d form the tetraspanin-associated uroplakin family, UPK2/3 [3,4,5,6,7].UPKs play important roles in the expansion and stabilization of the urothelial apical surface and contribute to the urothelium permeability barrier function in mammals [8]
We show that UPK2/3 proteins are related to and are probably derived from an ancestor R3 PTPRQ-like gene in invertebrates
The above observations indicate that UPK2/3 uroplakins are variations on a common structural theme with UPK2a and UPK2b genes losing the cytoplasmic tail, UPK3d gaining a pair of cyteines, and UPK2a and UPK3c losing cysteine pairs C3 and C4 and C1 and C2, respectively

Summary

Introduction

UPKs play important roles in the expansion and stabilization of the urothelial apical surface and contribute to the urothelium permeability barrier function in mammals [8] Their protein structure, function and involvement in urinary tract development and malformations are the subject of several reports and reviews [5,7,9,10,11,12,13,14,15,16]. PTPRQ belongs to subtype R3 phospho-tyrosine phosphatase receptors (R3 PTPRs), which like UPK2/3 uroplakins are single-spanning membrane proteins. They are much larger than UPK2/3 proteins, which consist of an extracellular moiety of less than 200 amino acids and a short cytoplasmic tail, absent in UPK2a and UPK2b [3,7,20]. R3 PTPRs comprise five members: PTPRB (VE-PTP), PTPRH (SAP-1), PTPRJ (DEP-1), PTPRO (GLEPP1) and PTPRQ (PTPS31) [21,22,23]

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Results

Conclusion