Disease relevance of PLEKHA1

• We reasoned that this effect could be due to binding of TAPB and TAPP to HIV-1 TAR RNA [1].
• The hernia repair was not classified as a standard operation (e.g. Shouldice, Lichtenstein, Plug/Mesh, TAPP/TEP) in 38.2 per cent of women and 11.2 per cent of men [2].
• The inguinal hernia repair might take the form of either total extraperitoneal hernioplasty (TEP) or transabdominal extraperitoneal hernioplasty (TAPP), with mesh placement [3].
• The TAPP method causes less rate of postoperative inguinal neuralgia than Lichtenstein repair, emphasizing more persistent discomfort in anterior approach than laparoscopic repair [4].
• The transabdominal laparoscopic (TAPP) route brings a potential risk of abdominal adhesions, which may increase the risk of postoperative intestinal obstruction [5].

High impact information on PLEKHA1

• All nonsynonymous SNPs in this critical region were genotyped, yielding a highly significant association (P < .00001) between PLEKHA1/LOC387715 and ARM [6].
• We identified a strong association signal overlying three genes, PLEKHA1, LOC387715, and PRSS11 [6].
• We report the characterization of two signal transduction proteins related to Bam32, known as TAPP1 and TAPP2 [7].
• Using live-cell imaging, we demonstrate that TAPP1 and TAPP2 are recruited to the plasma membrane of BJAB human B-lymphoma cells upon activation through the B-cell antigen receptor (BCR) [7].
• TAPP1 and TAPP2 are targets of phosphatidylinositol 3-kinase signaling in B cells: sustained plasma membrane recruitment triggered by the B-cell antigen receptor [7].

Chemical compound and disease context of PLEKHA1

• We found a block to Tat-induced HIV-1 transcription assessed by inhibition of CAT activity in HL3T1 cells at a concentration lower than the IC50 value, suggesting that molecules with three (TAPB) and four (TAPP) benzamidine rings could be useful against HIV-1 [1].

Biological context of PLEKHA1

• Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715 [8].
• A search for proteins that interact with TAPP1 identified the multi-PDZ-containing protein termed 'MUPP1', a protein possessing 13 PDZ domains and no other known modular or catalytic domains [PDZ is postsynaptic density protein (PSD-95)/Drosophila disc large tumour suppressor (dlg)/tight junction protein (ZO1)] [9].
• A yeast two-hybrid screen of a human brain cDNA library with the PSD-95, Discs-large, ZO-1 (PDZ) domain of gamma1-syntrophin yielded overlapping clones encoding the C terminus of TAPP1, a pleckstrin homology (PH) domain-containing adapter protein that interacts specifically with phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) [10].
• The results obtained give evidence (a) for inhibition of cell proliferation by TAPP-H; (b) for stronger antiproliferative activity of TAPP-halo derivatives; (c) for TAPP-mediated inhibition of accumulation of c-myc RNA sequences but not of HLA-DR alpha mRNA and DR antigens [11].
• At the concentrations of 30 and 45 microg/mL, TAPP showed 91.9 and 96.4% inhibition on lipid peroxidation of linoleic acid emulsion, respectively [12].

Anatomical context of PLEKHA1

• In the present study we demonstrate that stimulation of Swiss 3T3 or 293 cells with agonists that stimulate PtdIns(3,4)P2 production results in the marked translocation of TAPP1 to the plasma membrane [9].
• TAPP1 and TAPP2 transcripts are expressed in a variety of tissues including lymphoid tissues [7].
• Both TAPP1 and syntrophins were localized to PDGF-induced circular membrane ruffles in NIH-3T3 cells [10].
• The 4-phosphatase contains C2 domains, which bound PtdIns(3,4)P2, and C2-domain-deletion mutants lost PtdIns(3,4)P2 4-phosphatase activity, did not localize to endosomes or inhibit TAPP1 PH domain membrane recruitment [13].
• TEP is preferable to TAPP because of its lower complication and recurrence rates and in the authors' hands is the "best repair." TAPP should be reserved for patients with prior lower abdominal wall incisions that make the dissection of the peritoneum from the underside of the incision impossible [14].

Associations of PLEKHA1 with chemical compounds

• Association studies have identified a major risk variant within the complement factor H gene (CFH), and recent reports suggest that PLEKHA1/LOC387715 and the BF/C2 regions may be major risk loci for AMD as well [15].
• Here we describe the crystal structure of the PtdIns(3,4)P(2)-binding PH domain of TAPP1 at 1.4 A (1 A=0.1 nm) resolution in complex with an ordered citrate molecule [16].
• However, a glycine residue adjacent to the D-5 inositol-phosphate-binding site in DAPP1 is substituted for a larger alanine residue in TAPP1, which also induces a conformational change in the neighbouring residues [16].
• Structural comparisons between the phosphoinositide-binding loops of the C-PH crystal structure and the PH domains of DAPP1 and TAPP1, the N-terminal PH domain of pleckstrin and a recently described solution structure of C-PH are presented and discussed [17].
• In addition, also TAPP-related compounds containing 2 (DAPP) or 3 (TAPB) benzamidine residues retain inhibitory activity on the proliferation of WI-L2 cells [11].

Physical interactions of PLEKHA1

• Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1 [18].

Other interactions of PLEKHA1

• The combination of our analyses strongly implicates PLEKHA1/LOC387715 as primarily responsible for the evidence of linkage of ARM to the 10q26 locus and as a major contributor to ARM susceptibility [6].
• This study provides the first evidence that TAPP1 and PtdIns(3,4) P (2) could function to regulate the membrane localization of PTPL1 [18].
• Interestingly, coexpression of alpha1- or gamma1-syntrophin with TAPP1 prevented the blockade of circular ruffling [10].

Analytical, diagnostic and therapeutic context of PLEKHA1

• BACKGROUND: Between October 1992 and May 1996, 893 hernia repairs were performed at the Surgical Clinic in Mannheim: 448 (50%) using laparoscopy (TAPP-method) and 445 (50%) using the conventional anterior approach (Shouldice) [19].
• Enantiomeric separation of TAPP, H-Tyr-(D)Ala-Phe-Phe-NH(2), by capillary electrophoresis using 18-crown-6-tetracarboxylic acid as a chiral selector [20].
• The latter group consisted of laparoscopic TAPP repair (n=46) and open onlay patch repair (n=64) or plug and patch repair (n=65) [21].
• This multicenter study compared short-term results in patients treated by the laparoscopic transabdominal preperitoneal patch technique (TAPP; n = 518) and the Shouldice technique (n = 524) [22].

References