Disease relevance of PTPRA

• Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor [1].
• Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells [2].
• RT-PCR analysis confirmed that both splice variants of the extracellular domain of PTP alpha that vary by an insert of 9 amino acids are expressed in human islets and insulinoma cells (INS-1E, RIN1046-38) [3].
• Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo [4].
• In this study, an antisense RNA expression strategy was used to reduce LRP to undetectable levels in HT 1080 fibrosarcoma cells [5].

Psychiatry related information on PTPRA

• LRP in Alzheimer's disease: friend or foe [6]?
• Recent data indicate that the 37-kD precursor (LRP) for this molecule acts as a receptor for prion proteins (PrP), self-proteins implicated in the pathogenesis of transmissible spongiform encephalopathies including new variant Creutzfeldt-Jakob disease (nvCJD) [7].
• Behavioral methods (Reaction Time, RT) and two different Event Related Potential (ERP) components measuring i) stimulus selection (Selection Negativity, SN) and ii) response selection (Lateralized Readiness Potential, LRP) were employed [8].
• Studies using the lateralized readiness potential (LRP; an index of hand-specific motor preparation), suggest that the motor system can be activated on the basis of partial information, providing support for a parallel view of the human information processing system [9].

High impact information on PTPRA

• Complementation and RNA-interference experiments showed that PTPA fulfills an essential function conserved from yeast to man [10].
• PTPA binding to PP2A results in a dramatic alteration of substrate specificity, with enhanced phosphotyrosine phosphatase activity and decreased phosphoserine phosphatase activity [11].
• To understand the molecular mechanism of PTPA activity, Ypa1 was cocrystallized with a proline-containing PPIase peptide substrate [12].
• We conclude that Snx 17 binds to a motif in the LRP tail distinct from the endocytosis signals and promotes LRP sorting to the recycling pathway in the early endosomes [13].
• The NPxY motif, proximal to the plasma membrane in the LRP cytoplasmic tail, is identified as the Snx 17-binding motif [13].

Chemical compound and disease context of PTPRA

• PTPalpha-null animals had normal body weights and circulating levels of glucose and insulin in random fed and fasted states [14].
• Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands such as fatty acids and rosiglitazone increased functional cell surface LRP by 1.5-2.0-fold in primary human adipocytes and in the SW872 human liposarcoma cell line as assessed by activated alpha(2)-macroglobulin binding and degradation [15].
• In order to delineate the neuroprotective role of the low density lipoprotein receptor-related protein (LRP) against amyloid beta-protein toxicity, studies were performed in C6 cells challenged with amyloid beta-protein in the presence or absence of activated alpha(2)-macroglobulin [16].
• RESULTS: Lung Resistance-related Protein (LRP/MVP) was detected in SK-OV-3 cells but not in the other two ovarian cancer lines with different sensitivity to cisplatin [17].

Biological context of PTPRA

• Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo [18].
• In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src) [19].
• The transmembrane and catalytic nature of PTPalpha indicate that it likely forms the transducing element of the complex, and we postulate that the role of contactin is to assemble a phosphorylation-competent system at the cell surface, conferring a dynamic signal transduction capability to the recognition element [20].
• The HLPR genes is located on human chromosome 20, and the protein it encodes likely plays a fundamental role in the physiology of all cells as its expression appears to be ubiquitous [21].
• Among transmembrane protein-tyrosine-phosphatases, the membrane distal catalytic domain (D2) of protein-tyrosine-phosphatase alpha (PTP alpha) is unusual in having low but detectable activity in the absence of the membrane proximal catalytic domain (D1) [22].

Anatomical context of PTPRA

• Sequence of a cDNA encoding human LRP (leukocyte common antigen-related peptide) [23].
• Here we present the first data concerning the 37 LRP/p40 gene promoter activity and show that it is very active in a cervix carcinoma cell line [24].
• Studies in cultured cells have implicated protein tyrosine phosphatase alpha (PTPalpha) as a potential regulator of insulin signaling [14].
• Kinetics and extents of insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation were similar in wild-type and PTPalpha(-/-) liver, muscle, and adipose tissue [14].
• The effects of lactoferrin on collagen gel contraction and the activation of the signaling pathway were dependent on the expression of low-density lipoprotein receptor - related protein (LRP) - 1 in the fibroblasts [25].

Associations of PTPRA with chemical compounds

• We show a physical interaction of PI 3-kinase and PKCdelta with PTPalpha and show that the tyrosine phosphatase plays a role in the activation of MAPK [19].
• Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232 [19].
• A phosphotyrosine displacement mechanism for activation of Src by PTPalpha [26].
• We show that, dependent on serine hyperphosphorylation, protein tyrosine phosphatase alpha (PTPalpha) is activated by two different mechanisms during mitosis: its specific activity increases and its inhibitory binding to Grb2 decreases [27].
• Receptor protein tyrosine phosphatase alpha participates in the m1 muscarinic acetylcholine receptor-dependent regulation of Kv1.2 channel activity [28].

Regulatory relationships of PTPRA

• Receptor-like protein-tyrosine phosphatase alpha specifically inhibits insulin-increased prolactin gene expression [29].

Other interactions of PTPRA

• The cDNA clones thus isolated included LCA and six other novel receptor-like PTPases, named HPTP alpha, beta, gamma, delta, epsilon, and zeta [30].
• Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPalpha) is elevated and ERK is constitutively activated, several folds higher than that in parental cells [2].
• Overexpression of the wild type PTP alpha splice variant containing the 9 amino acids reduced insulin secretion, as did a mutant form unable to bind Grb2 (Tyr798Phe) [3].
• In accordance with these results, LAR content was significantly increased, whereas LRP content was not increased [31].
• As competitive inhibitors of PTP1B, ursolic acid and its derivative also inhibit T-cell protein tyrosine phosphatase and src homology phosphatase-2 but not leucocyte antigen-related phosphatase or protein tyrosine phosphatase alpha and epsilon, which are all possibly involved in the insulin pathway [32].

Analytical, diagnostic and therapeutic context of PTPRA

• This complex is stable to isolation from brain lysates or transfected cells through immunoprecipitation and to antibody-induced coclustering of PTPalpha and contactin within cells [20].
• The gene for receptor-linked protein-tyrosine-phosphatase (PTPA) is assigned to human chromosome 20p12-pter by in situ hybridization (ISH and FISH) [33].
• Characterization using surface plasmon resonance showed that calmodulin bound to PTPalpha-D2 in a Ca(2+)-dependent manner but did not bind to the membrane proximal catalytic domain (D1) of PTPalpha, to the two tandem catalytic domains (D1D2) of PTPalpha, nor to the closely related D2 domain of PTPepsilon [34].
• Using immunofluorescence double staining, we found that LRP and RAP colocalize in the same cells in the lesions studied and in the same cell structures in the cell lines studied [35].
• With flow cytometry, we found surface expression of LRP to be restricted to urokinase plasminogen activator, producing highly metastatic cell lines [35].

References