Disease relevance of KPNA2

• Here, we show that an early step of HIV-1 nuclear import is the recognition of the MA nuclear localization signal (NLS) by Rch1, a member of the karyopherin-alpha family [1].
• (ii) EBNA-1 proteins endogenous in the B cell line Raji of Burkitt lymphoma origin bound to another adaptor protein, karyopherin alpha2 (hSRP1alpha, hRch1), interactions of which to recombinant EBNA-1 polypeptides were previously reported [2].

High impact information on KPNA2

• A recombinant human protein, hSRP1 alpha, bound in vitro specifically and directly to substrates containing either a simple or bipartite NLS motif. hSRP1 alpha promoted docking of import substrates to the nuclear envelope and together with recombinant human Ran reconstituted complete nuclear protein import [3].
• Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1 [4].
• After nuclear injection, the truncated Rch1 was retained in the nucleus, but either Rch1 residues 207-217 or a heterologous nuclear export signal, but not a mutant form of residues 207-217, restored nuclear export [5].
• Loss of the nuclear transport factor RCC1 (regulator of chromosome condensation) at the nonpermissive temperature in the thermosensitive mutant cell line tsBN2 caused nuclear accumulation of wild-type Rch1 injected into the cytoplasm [5].
• In contrast, a mutant of Rch1 lacking the first 243 residues accumulated in the nuclei of Vero cells after cytoplasmic injection [5].

Biological context of KPNA2

• Human karyopherin alpha2 (KPNA2), a member of the karyopherin alpha family, plays a key role in the nuclear import of proteins with a classical nuclear localization signal (NLS) [6].
• Here, we present the genomic organization of the human KPNA2 gene with 11 exons spanning approximately 10 kb on chromosome 17q23-q24 [6].
• Importin KPNA2, NBS1, DNA Repair and Tumorigenesis [7].
• The acetylation site within Rch1 was mapped to a single residue, Lys22 [8].
• In addition, metabolic activation led to a redistribution of Rch1 from the cytoplasm to both the plasma membrane and the nuclear interior [9].

Anatomical context of KPNA2

• KPNA2, as part of a karyopherin alpha-beta heterodimer, directly binds to the NLS of proteins and functions as an adaptor that binds NLS-containing proteins via karyopherin beta to the nuclear pore complex [6].
• A truncated form of Rch1, which retains the ability to interact with RAG-1, reduces V(D)J recombination activity in HeLa cells [10].
• 4.1R80 was efficiently imported in the nuclei of digitonin-permeabilized COS-7 cells in the presence of recombinant Rch1 (human importin alpha2), importin beta, and GTPase Ran [11].
• Furthermore, in HeLa cell crude cytosol, it was found that endogenous Rch1 binds to all the tested NLS substrates, while the binding of endogenous NPI-1 is restricted to only some NLSs, despite the fact that NPI-1 itself shows binding activity to a variety of NLSs [12].
• We observed that the level of Rch1 increases dramatically, especially in larger lymphocytes, in response to activation [9].

Associations of KPNA2 with chemical compounds

• The expression of short interfering RNA of Rch1 suppressed suberoylanilide hydroxamic acid-induced nuclear accumulation of TBP-2 [13].
• The physical interaction between TBP-2 and Rch1 was confirmed with a glutathione S-transferase pull-down assay [13].
• Mutagenesis of the glycine, as well as the lysine, severely impaired Rch1 acetylation, supporting the view that GK is part of a recognition motif for acetylation by CBP/p300 [8].
• RESULTS: We have coupled a 62-aminoacid peptide derived from hSRP1alpha importin beta binding domain, called the IBB peptide to plasmid DNA by using the heterobifunctional linker N-(4-azido-2,3,5,6 tetrafluorobenzyl)-6-maleimidyl hexanamide (TFPAM-6) [14].

Physical interactions of KPNA2

• To investigate the mechanism underlying the nuclear localization, we performed a yeast two-hybrid screening and identified importin alpha(1) (Rch1) as a protein interacting with TBP-2 [13].
• Two-hybrid experiments revealed that Qip1 interacted with the NLS of SV40 T antigen similar to Rch1 and hSrp1 [15].

Other interactions of KPNA2

• Rch1, a protein that specifically interacts with the RAG-1 recombination-activating protein [10].
• Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1 [16].
• We report here that the KPNA2 (importin alpha1) is important for the normal nuclear localization of the MRN complex and its proper formation of the nuclear foci [16].
• Genomic structure of karyopherin alpha2 ( KPNA2) within a low-copy repeat on chromosome 17q23-q24 and mutation analysis in patients with Russell-Silver syndrome [6].
• Importin alpha1 (Rch1) mediates nuclear translocation of thioredoxin-binding protein-2/vitamin D(3)-up-regulated protein 1 [13].

Analytical, diagnostic and therapeutic context of KPNA2

• Using the yeast two-hybrid assay, we have identified RCH1, a gene encoding a protein of molecular weight 58,000 that interacts specifically with RAG-1 [10].
• By quantitative RT-PCR, the average mRNA expression levels of these four genes in 20 primary ECs were 2.7-fold (PLK), 6.1-fold (survivin), 2.6-fold (KPNA2), and 2.4-fold (PTTG1) higher than that of each gene in 24 different normal organs [17].

References