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

Date Published: January 18, 2017

Publisher: Public Library of Science

Author(s): Javier U. Chicote, Rob DeSalle, José Segarra, Tung-Tien Sun, Antonio García-España, Manuela Helmer-Citterich.


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.

Partial Text

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 (also known as UPII, encoded by the UPK2 gene), UPK2b (non-mammalian vertebrates), UPK3a (UPIIIa, UPK3A), UPK3b (UPIIIb, UPK3B), UPK3c (UPK3BL; present in mammals, reptiles and birds) and UPK3d (bony fish) form the tetraspanin-associated uroplakin family, UPK2/3 [3–7].

The discovery that UPK2/3 proteins are most likely derived from an ancestral PTPRQ gene by gene duplication and domain loss and that UPK2/3 and R3 PTPR genes share a juxtamembrane long FN3 domain with conserved structural characteristics will facilitate further studies on the structure and function of these important proteins with implications in human disease.




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