Disease relevance of Axin1

• Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells [1].
• The fibrosarcoma IC9 is deficient in the expression of the major histocompatibility complex class I genes Kb, Kk, and Dk and expresses only the Db molecule [2].
• Wild-type and delta Ki mutant PDGF receptor proteins expressed with recombinant baculovirus vectors also associated in vitro with mammalian PLC-gamma [3].
• Transfection of the highly metastatic lines with cloned H-2K genes (Kb, Kk) reduced their tumorigenicity and abolished the formation of metastasis in syngeneic mice, while the transfection of the nonmetastatic lines with cloned H-2Dk genes resulted in shifting the cells to the metastatic phenotype [4].
• Our results indicate that the HLA-A*0201/Kb transgenic mouse is a useful animal model to perform preclinical testing of potential cancer vaccines, and that Melan-A peptide analogues are attractive candidates for melanoma immunotherapy [5].

High impact information on Axin1

• The clustered changes in the mutant genes are consistent with the hypothesis that genetic recombination between class-I genes generates the Kb mutants [6].
• Genealogical analysis of several bm mutants has further indicated that at least some, if not all, of the gene interaction events generating Kb mutations occurred during mitotic amplification of the germ cells [6].
• Here, we show that presenilin functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1alpha complex [7].
• Analysis of T-cell subsets in rejection of Kb mutant skin allografts differing at class I MHC [8].
• When Wnt signaling in preadipocytes is prevented by overexpression of Axin or dominant-negative TCF4, these cells differentiate into adipocytes [9].

Biological context of Axin1

• Mice with deletion of Axin1 exhibit defects in axis determination and brain patterning during early embryonic development [10].
• Axin is required for axon formation and extension of cortical neurons during the development of mouse cerebral cortex [11]
• Axin binds with GSK-3beta to promote axon formation in cortical neurons [11].
• Introduction of a point mutation into full-length Axin that prevented GSK-3beta binding also generated a transcriptional activator [12].
• Both Axin(Ax/Ax) and Axin(Ax2/Ax2) homozygotes are apparently normal and fertile, demonstrating that the Axin and Axin2 proteins are functionally equivalent [13].
• Fused (Fu) is a dominant mutation in mice resulting in the asymmetry and fusion of tail vertebrae in heterozygotes [14].
• There are two more severe alleles at Fu, Kinky (FuKi) and Knobbly (FuKb), which die between 9 and 10 days of gestation as homozygotes, exhibiting a duplication of the embryonic axis, leading to incomplete or complete twinning [14].

Anatomical context of Axin1

• Although Axin2 is also highly expressed during early neural development, including the neural tube and neural crest, it is not essential for these processes, apparently due to functional redundancy with Axin1 [15].
• Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane [16].
• Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL [17].
• Differentiation of skin stem cells into hair follicles (HFs) requires the inhibition of beta-catenin degradation, which is controlled by a complex containing axin and the protein kinase GSK3beta [18].
• Immature thymocytes underwent massive apoptosis, indicating that the overexpression of Axin blocks the normal development of T lymphocytes [19].

Associations of Axin1 with chemical compounds

• Reverse transcription-PCR and Western blot analysis showed that Axin is expressed in undifferentiated cells, whereas the level is clearly reduced during RA-induced neuronal differentiation [20].
• Interestingly, Axin, which is also a substrate for GSK-3, was destabilized by Li(+) and ectopic expression of Axin inhibited Li(+)-induced neurite outgrowth [1].
• To study the role of Axin in development, we developed strains of transgenic mice in which its expression can be manipulated by the administration of doxycycline (Dox) [19].
• We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action [21].
• The interaction of CK1alpha from Danio rerio with mouse-axin has been studied using a pull-down assay that uses fragments of axin fused to glutathione S transferase, which is bound to glutathione sepharose beads [22].

Physical interactions of Axin1

• Expression of a 59 amino acid GSK-3beta-binding region from Axin strongly activated transcription in the absence of an upstream signal [12].
• The direct interaction between Axin and GSK-3beta facilitates GSK-3beta inactivation in neurons through recruiting GSK-3beta to its upstream kinase Akt [11].
• Idax and Axin competed with each other for the binding to Dvl [23].
• As a consequence, beta-catenin is no longer bound to Axin or phosphorylated by glycogen synthase kinase-3, resulting in TCF-1 activation [24].

Regulatory relationships of Axin1

• Axin apparently regulates beta-catenin in coordinating cell cycle progression, cell adhesion and survival of neuroepithelial precursors during development of ventricles [15].
• Axin is phosphorylated by cyclin-dependent kinase 5 (Cdk5) during mouse brain development. This phosphorylation directs axon formation in developing cortical neurons [11]. Growth factors, such as neurotrophins, promote axon development in cortical neurons through enhancing the Cdk5-mediated Axin phosphorylation [11].

Other interactions of Axin1

• Deletion analysis suggested that Dvl-association determinants within Axin were contained between residues 603 and 810 [12].
• Mouse axin and axin2/conductin proteins are functionally equivalent in vivo [13].
• When Dvl-2 localization was altered using a C-terminal CAAX motif, Axin was also redistributed, suggesting a close association between the two proteins, a conclusion supported by co-immunoprecipitation data [12].
• In the absence of Wnt, MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC [16].
• The genetics of the fused (Fu) gene in the house mouse, Mus musculus, was studied by use of the closely linked recessive marker, tufted (tf) [25].

Analytical, diagnostic and therapeutic context of Axin1

• As the sequence analysis of the coding region for the first 273 amino acid residues shows identity between parent and mutant except for the seven nucleotide changes, all variant-parent functional differences must depend only on the cluster of three amino acid differences in the second domain of the Kb glycoprotein [26].
• In A2/Kb transgenic mice that express alpha1 and alpha2 domains of human HLA-A*0201, vaccination using these epitope peptides in vivo was associated with significant suppression of the tumor growth and prolongation of the animal survival without fatal adverse effects [27].
• The presence of a specific H-4 peptide was confirmed when the radiolabeled peptide mix eluted from Kb molecules was separated by HPLC [28].
• H-2 antigen variants generated by chemical mutagenesis of a cell line expressing the H-2b haplotype were first selected with alloantisera for their loss of H-2Kb expression, and then were analyzed by radioimmunoassay for the appearance of intracellular Kb antigen [29].
• The clone contains 677 nucleotides, and, as shown by northern blotting, is derived from a 1.5 Kb poly(A)+ mRNA [30].

References