Disease relevance of Plek

• 3BP2 is a pleckstrin homology domain- and Src homology 2 (SH2) domain-containing adapter protein that is mutated in the rare human bone disorder cherubism and which has also been implicated in immunoreceptor signaling [1].

High impact information on Plek

• Vav contains an array of structural motifs that include Src-homology domains SH2/SH3 and regions of homology to the guanine-nucleotide-exchange protein Dbl, pleckstrin and protein kinase C (refs 5-9) [2].
• In contrast, the conserved tyrosine near the COOH terminus is dispensable and the pleckstrin homology domain of Lnk contributes to, but is not essential for, inhibiting Tpo-dependent 32D cell growth or megakaryocyte development [3].
• We have used a GFP-tagged pleckstrin homology domain to visualize IP(3) dynamics in Purkinje cells [4].
• We used imaging of fluorescent chimeras of pleckstrin homology and C1 domains in live macrophages to monitor the distribution of phosphatidylinositol-4,5-bisphosphate (4,5-PIP(2)) and diacylglycerol, respectively, during phagocytosis [5].
• Visualization of phosphoinositides that bind pleckstrin homology domains: calcium- and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools [6].

Biological context of Plek

• Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors [7].
• Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module [8].
• Gab2 is an adaptor molecule containing a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains [9].
• Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interaction [10].
• Our findings suggest that pleckstrin may serve as an intracellular adaptor/targeting protein in response to particulate stimuli [11].

Anatomical context of Plek

• Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase [12].
• In the wild-type neutrophils, the pleckstrin homology domain-containing protein kinase B (AKT) and F-actin colocalize to the leading edge of polarized neutrophils oriented toward the gradient, which was not observed in PI3Kgamma(-/-) neutrophils [13].
• The spatial and temporal dynamics of pleckstrin homology domain binding at the plasma membrane measured by imaging single molecules in live mouse myoblasts [14].
• Thus, association of pleckstrin with phagosomes is independent of its phosphorylation [11].
• In fibroblasts, Tiam1 induces Rac-mediated membrane ruffling, which requires the N-terminal pleckstrin homology (PHn) domain [15].

Associations of Plek with chemical compounds

• Deletion of the N-terminal region containing the pleckstrin homology domain did not affect RAC-PK activation by okadaic acid, but it reduced vanadate-stimulated activity and also blocked the serum-induced activation [7].
• The functions of Dok-1 have now been investigated by the generation of two different COOH-terminal truncation mutants of this protein: one (DokPH+PTB) containing the pleckstrin homology and phosphotyrosine-binding domains, and the other (DokPH) composed only of the pleckstrin homology domain [16].
• The feasibility of the screen was initially demonstrated using avidin-coated beads prebound to biotinylated PtdIns-3,4-P(2) and PtdIns-3,4,5-P(3) to specifically isolate the pleckstrin homology domain of the serine/threonine kinase Akt [17].
• Second, using a construct lacking this pleckstrin homology domain, which does not require translocation for activation, we found that ceramide stimulates the dephosphorylation of Akt/PKB by protein phosphatase 2A [18].
• Serum- and glucocorticoid-regulated kinase (SGK) is a serine kinase that has a catalytic domain homologous to that of Akt, but lacks the pleckstrin homology domain present in Akt [19].

Physical interactions of Plek

• Deletion of the pleckstrin and phosphotyrosine binding domains of insulin receptor substrate-2 does not impair its ability to regulate cell proliferation in myeloid cells [20].

Regulatory relationships of Plek

• These results indicate that Akt1 and 3 are similarly stimulated by insulin and this stimulation is inhibited by prior activation of protein kinase C through a mechanism that is independent of the presence of the pleckstrin homology domain [21].
• Pleckstrin expression in mouse macrophages was induced severalfold in response to bacterial LPS and IFN-gamma [11].

Other interactions of Plek

• Using several mutant forms of Mtmr2, we identified two domains that are necessary for membrane association: (i) A pleckstrin homology-GRAM domain; and (ii) a coiled-coil module [8].
• Targeting of Tiam1 to the plasma membrane requires the cooperative function of the N-terminal pleckstrin homology domain and an adjacent protein interaction domain [15].
• Akt2 encodes a protein-serine/threonine kinase containing a pleckstrin homology domain characteristic of many signaling molecules [22].
• Since this inhibition could have resulted from an interaction of the pleckstrin homology domain of the Akt with protein kinase C, we also examined the ability of a mutant Akt1 lacking this domain to be regulated by this enzyme [21].
• The amino-terminal pleckstrin homology (PH) domain of IRS-1 plays a pivotal role in promoting insulin receptor (IR)-IRS-1 protein interactions [23].

Analytical, diagnostic and therapeutic context of Plek

• Binding of a Pleckstrin homology domain protein to phosphoinositide in membranes: a miniaturized FRET-based assay for drug screening [24].

References