Disease relevance of Kpna6

• Intriguingly, the bNLS is highly conserved among Dengue and related flaviviruses, implying a general role for the region and importin beta in the infectious cycle [1].
• The protein kinase CK2 site (Ser111/112) enhances recognition of the simian virus 40 large T-antigen nuclear localization sequence by importin [2].
• This is the first report of the importin binding and nuclear import properties of a gene product from a negative sense RNA virus, with implications for the function of RSV M and possibly other viral M proteins in the nucleus of infected cells [3].
• Nuclear import of the respiratory syncytial virus matrix protein is mediated by importin beta1 independent of importin alpha [3].
• Nuclear import studies on microinjected and permeabilized rat hepatoma cells demonstrated functionality of the NLS in nuclear targeting, with inhibition by antibodies demonstrating the requirement of both importin alpha and beta for nuclear import of kanadaptin [4].

High impact information on Kpna6

• Here we show that this nuclear pore targeting complex initially docks as a single entity to the nuclear pore via importin-beta [5].
• In contrast, importin-beta accumulates at the nuclear envelope, but not in the nucleoplasm [5].
• As the first event, the complex of importin-alpha and importin-beta binds the import substrate in the cytosol [5].
• Our data indicate that protein VI shuttles between the nucleus and the cytoplasm and that it links hexon to the nuclear import machinery via an importin alpha/beta-dependent mechanism [6].
• Comparison with the crystal structure of FG-nucleoporin cores bound to importin-beta and TAP/p15 identified a number of common features of their binding sites [7].

Biological context of Kpna6

• These nucleoporins are proposed to provide progressively more distal binding sites for importin beta during import [8].
• We conclude that the Dorsal NLS and PKA site constitute a phosphorylation-regulated NLS essential to Dorsal function and able to function in heterologous mammalian cell systems, where phosphorylation modulates the affinity of NLS recognition by importin [9].
• We have studied the function of four conserved tryptophans of importin beta (Trp-342, Trp-430, Trp-472, and Trp-864) located at the binding interface with the IBB domain by systematic alanine substitution mutagenesis [10].
• The present study examines and correlates for the first time the effect of the lysine/nucleotide (Ly/Nu) ratio on transfection, recognition by importin alpha/beta, and structure as determined using electron microscopy (EM) and atomic force microscopy (AFM), for pLy-DNA complexes with and without NLSs or mutant versions thereof [11].
• CONCLUSIONS: A specific importin alpha isoform up-regulation takes place in kidneys of diabetic rats [12].

Anatomical context of Kpna6

• We demonstrate that KIFC1 is associated with importin beta and colocalizes with this nuclear transport factor on curvilinear structures associated with the spermatid nuclei [13].
• By isolating nuclei of PC12 cells and immunoprecipitating aPKC with Ab-PY256, we observed that Tyr256 is rapidly phosphorylated upon NGF treatment prior to entry of aPKC into the nucleus. aPKC was observed to exclusively bind to importin-beta [14].
• Phorbol ester-induced differentiation of human leukemia (HL60) cells towards a macrophage phenotype led to downregulation of importin alpha1 and alpha4 expression after 72 hours [15].
• Importin beta1 mediates the glucose-stimulated nuclear import of pancreatic and duodenal homeobox-1 in pancreatic islet beta-cells (MIN6) [16].

Associations of Kpna6 with chemical compounds

• The results indicate a clear correlation between the pLy-DNA structure, importin alpha/beta recognition, and gene transfer efficiency, thus underlining the importance of using pLy-DNA at the optimal Ly/Nu ratio [11].
• We have recently shown that cross-linking nuclear localization sequences (NLSs) to pLy can enhance transfection by conferring specific recognition by the cellular nuclear import 'receptor', the NLS-binding importin alpha/beta heterodimer [11].
• Using native PAGE, ELISA-based binding assays, a novel Alphascreen assay, and an in vitro nuclear transport assay, we show that M is recognized directly by the importin beta1 nuclear import receptor, which mediates its nuclear import in concert with the guanine nucleotide-binding protein Ran [3].
• The interaction between importin-beta and aPKC was enhanced upon tyrosine phosphorylation of aPKC and binding was abrogated when Tyr256 was mutated to phenylalanine [14].
• Stimulation of rat pancreatic AR42J cell differentiation towards a neuroendocrine phenotype with activin A or towards an acinar phenotype with dexamethasone, caused strong upregulation of importin alpha3 and alpha4 expression [15].

Analytical, diagnostic and therapeutic context of Kpna6

• Immunoelectron microscopy detects importin-beta on both sides of the nuclear pore [5].
• We have used immunoprecipitation to identify physiologically relevant complexes of nucleoporins and importin subunits [17].
• Quantitation of NLS recognition by the importin 58/97 subunits using an enzyme-linked immunosorbent assay indicated that while the Ala120 protein derivative had a binding affinity very similar to that of wild type, the Asp120 derivative showed 40% higher affinity [18].
• Also, using an anti-importin beta antibody, Western blots detected importin beta at 94 kDa [19].
• Using immunoprecipitation and affinity chromatography, we show that the PTH1R forms a complex with the importin family of transport molecules [19].

References