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

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.

Circular DNA intermediates in the generation of large human segmental duplications

“…1 B). After an initial unexpected observation of this type of rearrangement in the loci of UPK3C , which codes for a highly expressed corneal protein recently characterized by some of us [ 16 , 17 ], we identified (see methods) four inter-chromosomal and twenty intra-chromosomal pairs of human SD clusters with this specific rearrangement including the X-Y transposed region (SD cluster 6) [ 18 ] and the Williams syndrome locus (SD cluster 16) [ 19 , 20 ] (Table S 1 and Figure S 1 ). Each duplication block A-B and C-D consists of at least of one annotated SD, more if insertions, deletions and/or inversions have occurred during their evolutionary history (Table S 1 and Figure S 1 ).…”

Circular DNA intermediates in the generation of large human segmental duplications.

“…This speci c change in the segments block order will generate two parallel identity slant lines in homology plots of the duplicated sequences ( Figure 1B). After an initial unexpected observation of this type of rearrangement in the loci of UPK3C, which codes for a highly expressed corneal protein recently characterized by some of us [16,17], we identi ed (see methods) four inter-chromosomal and twenty intra-chromosomal pairs of human SD clusters with this speci c rearrangement including the X-Y transposed region (SD cluster 6) [18] and the Williams syndrome locus (SD cluster 16) [19,20] (Table S1and Figure S1). Each duplication block A-B and C-D consists of at least of one annotated SD, more if insertions, deletions and/or inversions have occurred during their evolutionary history (Table S1 and Figure S1).…”

Uroplakins play conserved roles in egg fertilization and acquired additional urothelial functions during mammalian divergence

“…On the basis of the fully sequenced genomes of a broad array of chordates (cephalochordats, urochordates, and vertebrates), we have previously analyzed the evolution of uroplakin genes and showed that they originate in the common ancestor of vertebrates (Garcia-Espana et al , 2006; Desalle et al , 2014; Chicote et al , 2017). Analyses of the vertebrate uroplakin sequences revealed many mammal-specific residues interspersed by residues that are common to all (mammalian and nonmammalian) uroplakins (Figure 8, A and B, and Supplemental Figure S6) (Desalle et al , 2014).…”

“…(C) Model depicting the evolution of all the known uroplakin genes. Symbols: red arrows (genealogical relationship), two-headed black arrows (protein–protein interaction), asterisk (a strong pattern of significant skew towards dN / dS >1.0 suggesting possible selection that accompanies the duplication events that produced the paralogue group) (Desalle et al , 2014), phosphotyrosine phosphatase receptor (PTPR) (Chicote et al , 2017), tetraspanin precursor (TM4), million years (MY). See main text for details.…”