Disease relevance of PTPRD

• The PTPRD (protein tyrosine phosphatase receptor type D) locus at 9p23 was the second-most frequently deleted (8/78, 10%), and the deletions were detected in both small-cell lung carcinomas (SCLC) and NSCLC [1].
• High-resolution analysis of chromosomal breakpoints and genomic instability identifies PTPRD as a candidate tumor suppressor gene in neuroblastoma [2].
• In addition to previously characterized loci, two regions of homozygous deletion were found, one near the PTPRD locus on chromosome segment 9p23 in four samples representing both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) and the second on chromosome segment 3q25 in one sample each of NSCLC and SCLC [3].
• Metabolism of haloperidol and its tetrahydropyridine dehydration product HPTP [4].
• We have attempted to find out any relationships between circulating tumor necrosis factor (TNF)-alpha levels and Epstein-Barr virus (EBV) associated peripheral T-cell and NK-cell proliferative disease/lymphoma (PTPD/L) status [5].

High impact information on PTPRD

• HPTP delta is very similar to leukocyte common antigen related molecule (LAR), in both the extracellular and cytoplasmic regions [6].
• Short isoforms of both HPTP sigma and HPTP delta were also detected that contain only four of the eight fibronectin type III-like domains [7].
• Multiple isoforms of LAR, HPTP delta, and HPTP sigma appear to be generated by tissue-specific alternative splicing of up to four mini-exon segments that encode peptides of 4-16 aa located in both the extracellular and intracellular regions [7].
• The second catalytic domain of protein tyrosine phosphatase delta (PTP delta) binds to and inhibits the first catalytic domain of PTP sigma [8].
• MPTP delta, a putative murine homolog of HPTP delta, is expressed in specialized regions of the brain and in the B-cell lineage [9].

Chemical compound and disease context of PTPRD

• The neuroleptic agent haloperidol (HP) and its tetrahydropyridine dehydration product HPTP are biotransformed to the potentially neurotoxic HP pyridinium species HPP+ and the reduced HP pyridinium species RHPP+ in humans and rodents [10].

Biological context of PTPRD

• Reverse transcription polymerase chain reaction analysis demonstrated that HPTP delta isoforms lacking these short peptides are expressed in kidney, whereas isoforms containing these peptides are expressed in the brain [11].
• The results clearly demonstrated that HPTP delta gene maps to human chromosome 9p24 [12].
• Its deduced amino acid sequence of 642 residues was 94.6% identical to C-terminal 642 residues of human PTP epsilon (HPTP epsilon) [13].
• One of the functions of PTPases is to reverse the effect of protein tyrosine kinases (PTKases), many of which are oncogenes, suggesting that they may act as tumor suppressors as described for HPTP gamma [14].
• In vitro metabolic studies employing tissue preparations isolated from rodents, baboons and humans have documented that cytochrome P4503A enzymes catalyze the biotransformation of both HP and HPTP to yield the corresponding pyridinium metabolite HPP+ [15].

Anatomical context of PTPRD

• Microsomes prepared from a human lymphoblastoid cell line co-expressing human P450 3A4 and cytochrome P450 reductase also catalyzed the formation of HPP+ from HP and HPTP [10].
• We conclude that the conversions of HP and HPTP to potentially neurotoxic pyridinium metabolite HPP+ are catalyzed selectively by P450 3A4 in human liver microsomes [10].
• The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment [16].

Associations of PTPRD with chemical compounds

• Increased lipophilicity of haloperidol metabolites did not correlate with inhibitory potency since the more lipophilic HPTP metabolite was less potent as an inhibitor than reduced-haloperidol and reduced-HPTP [17].
• Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study [16].
• These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment [16].
• Chromosomal assignment of the gene for protein tyrosine phosphatase HPTP delta [12].
• The 1,2,3,6-tetrahydropyridine scaffold was chosen due to its common occurrence in the structures of CYP2D6 ligands such as the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the dehydrated haloperidol metabolite N-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (HPTP) [17].

Physical interactions of PTPRD

• The full-length HPTP delta isoform has an extracellular region containing three Ig-like and eight FN-III-like domains connected via a transmembrane peptide to an intracellular region with two PTPase domains, whereas another isoform lacks four of the eight FN-III like domains [11].

Other interactions of PTPRD

• Mutational analysis of the HPTP delta proprotein cleavage site revealed the existence of two or three functional and overlapping furin-like endoprotease cleavage sites [11].

Analytical, diagnostic and therapeutic context of PTPRD

• Furthermore, HPLC tracings reveal the presence of HPP+, RHPP+, and two phenolic pyridinium metabolites in brain tissue extracts of HPTP, but not HP, treated mice [18].
• The 1-MeTIQ contents in mouse brains following intraperitoneal administration of HP or its dehydrated product, HPTP (1 and 4 mg/kg per day, for four days), were markedly reduced compared with control groups [19].

References