Disease relevance of SLC20A2

• The type III sodium-dependent phosphate (NaPi) cotransporter, Pit2, is a receptor for amphotropic murine leukemia virus (A-MuLV) and 10A1 MuLV [1].
• We substituted extracellular regions of HaPiT2 for those of PiT2 to map the region of the HaPiT2 protein required for GALV receptor function [2].
• RNA levels of human retrovirus receptors Pit1 and Pit2 do not correlate with infectibility by three retroviral vector pseudotypes [3].
• Three distinct envelope domains, variably present in subgroup B feline leukemia virus recombinants, mediate Pit1 and Pit2 receptor recognition [4].
• PiT-2 also functions as a retroviral receptor, and functional membrane-localized protein was confirmed throughout the dental papilla/pulp by demonstrating cellular permissiveness to infection by a gammaretrovirus that uses PiT-2 as a receptor [5].

High impact information on SLC20A2

• Type III sodium-dependent phosphate (NaP(i)) cotransporters, Pit1 and Pit2, have been assigned housekeeping P(i) transport functions and suggested involved in chondroblastic and osteoblastic mineralization and ectopic calcification [6].
• Thus exchanging two putative transmembranic glutamate residues in human Pit2, Glu(55) and Glu(575), with glutamine or with lysine severely impaired or knocked out, respectively, P(i) transport function, but left viral receptor function undisturbed [6].
• The pit2- strain was moderately and the pit1-/pit2- strain strongly attenuated in virulence in mouse models of pulmonary and systemic infection, showing that the pit loci play a critical role during in vivo growth of S. pneumoniae [7].
• Human PiT2 (PiT2) is a multiple-membrane-spanning protein that functions as a type III sodium phosphate cotransporter and as the receptor for amphotropic murine leukemia virus (A-MuLV) [8].
• We have mutated a serine residue conserved in almost all of the 192 known PD001131 sequences to alanine in each PD001131 domain of human Pit2 [9].

Chemical compound and disease context of SLC20A2

• We have now determined that the substitution of a single amino acid residue, glutamic acid, for the lysine residue at position 522 in the fourth extracellular region of the PiT2 protein is sufficient to render PiT2 functional as a GALV receptor [2].

Biological context of SLC20A2

• Comparison of the deduced amino acid sequences of the HaPiT2 and PiT2 proteins suggested that differences in the amino acid composition of the extracellular region(s) of the hamster and human proteins account for their functional differences [2].
• We therefore examined the temporospatial expression patterns of Pit2 during murine odontogenesis [5].
• This assignment is in agreement with the fourth extracellular loop being outside the cell, consistent with the proposal that the fourth extracellular loop of GLVR-2 contains the envelope binding site [10].
• In contrast, the efficiency of phosphate uptake and retrovirus entry was inversely related to the extracellular phosphate concentration, indicating that PIT-2 activities are modulated by posttranslational modifications of cell surface molecules induced by phosphate [11].
• Thus, while FeLV-Bs that are able to use feline Pit2 can evolve by recombination with endogenous sequences, a subsequent point mutation during reverse transcription may be needed to generate a virus that can efficiently enter the cells using the feline Pit2 as its receptor [12].

Anatomical context of SLC20A2

• Using CHO cells expressing physiological amounts of functional versions of human Pit2 fused to various tagging epitopes, we provide evidence that Pit2 forms assemblies at the cell surface [13].
• We changed either of the highly conserved aspartates, Asp28 and Asp506, in the N- and C-terminal signature sequences, respectively, of human PiT2 to asparagine and analyzed P(i) uptake function in Xenopus laevis oocytes [14].
• MuLV-10A1 can utilize both Pit1 and Pit2 for entry into cells but could not infect any of the 14 human cell lines more efficiently than A-MuLV or GaLV [3].
• The superior transduction efficacy of CD8+ T cells by MuLV-10A1 correlates with a longer half-life of this pseudotype in comparison with A-MuLV and, as shown by interference analysis with the human T cell line HUT78, by the utilization of both the A-MuLV receptor (Pit2) and the GaLV receptor (Pit1) for cell entry [15].
• Both PiT-1 and PiT-2 are widely distributed in many tissues including kidney, brain, heart, liver, muscle, and bone marrow [16].

Associations of SLC20A2 with chemical compounds

• Thus the presence of an aspartic acid in either of the PiT family signature sequences is critical for the Na+-dependent P(i) transport function of human PiT2 [14].
• Here we show that an arginine at position 73 within variable region A (VRA) of the FeLV-B envelope surface unit (SU) is necessary for viral entry into cells via the human Pit2 receptor [17].
• However, the substitution of serine for methionine at position 138 (S138M) in a Pit1 chimera containing domain II of Pit2 resulted in a 1,000-fold reduction in A-MuLV receptor function [18].
• Receptor-deficient Chinese hamster ovary (CHO) cells were transfected with a PiT-2 construct that could be induced by the removal of tetracycline [19].
• We have additionally analyzed whether membrane fusion between HIV-like particles can be mediated by amphotropic murine leukemia virus (MuLV) glycoprotein and its respective cellular receptor, PiT-2 [20].

Other interactions of SLC20A2

• The primary structure of PIT-2 beta-lactamase was compared with those of two closely related enzymes, namely TEM-1 beta-lactamase and the beta-lactamase of Klebsiella pneumoniae strain LEN-1 [21].
• They were then categorised as periodontally healthy (PIT 0), with gingivitis but no pocketing exceeding 4 mm (PIT 1), with pocketing 4-5 mm (PIT 2), or with 6 mm + pocketing (PIT 3) [22].

Analytical, diagnostic and therapeutic context of SLC20A2

• Expression of this protein (GLVR-2) is likely to be a requirement for infection of human cells by amphotropic retroviral vectors for purposes of gene therapy [23].
• The gibbon ape leukemia virus (GaLV) and the amphotropic murine leukemia virus (A-MuLV) infect human cells via specific receptors, Pit1 and Pit2, respectively. mRNA levels of these receptors were determined by Northern analysis and for Pit2 in addition by quantitative RT-PCR [3].
• We further investigated the influence of domain II with respect to A-MuLV receptor function by performing site-specific mutagenesis within this region of Pit2 [18].

References