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Neurite outgrowth involves adenomatous polyposis coli protein and beta-catenin.

ABSTRACT: Neuronal morphogenesis involves the initial formation of neurites and then differentiation of neurites into axons and dendrites. The mechanisms underlying neurite formation are poorly understood. A candidate protein for controlling neurite extension is the adenomatous polyposis coli (APC) protein, which regulates membrane extensions, microtubules and beta-catenin-mediated transcription downstream of Wnt signaling. APC is enriched at the tip of several neurites of unpolarized hippocampal neurons and the tip of only the long axon in polarized hippocampal neurons. Significantly, APC localized to the tip of only one neurite, marked by dephospho-tau as the future axon, before that neurite had grown considerably longer than other neurites. To determine whether neurite outgrowth was affected by beta-catenin accumulation and signaling, a stabilized beta-catenin mutant was expressed in PC12 cells, and neurite formation was measured. Stabilized beta-catenin mutants accumulated in APC clusters and inhibited neurite formation and growth. Importantly, these effects were also observed was independently of the gene transcriptional activity of beta-catenin. These results indicate that APC is involved in both early neurite outgrowth and increased growth of the future axon, and that beta-catenin has a structural role in inhibiting APC function in neurite growth.

SUBMITTER: Votin V

PROVIDER: S-EPMC3373789 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Neurite outgrowth involves adenomatous polyposis coli protein and beta-catenin.

Votin Violet V Nelson W James WJ Barth Angela I M AI

Journal of cell science 20051122 Pt 24

Neuronal morphogenesis involves the initial formation of neurites and then differentiation of neurites into axons and dendrites. The mechanisms underlying neurite formation are poorly understood. A candidate protein for controlling neurite extension is the adenomatous polyposis coli (APC) protein, which regulates membrane extensions, microtubules and beta-catenin-mediated transcription downstream of Wnt signaling. APC is enriched at the tip of several neurites of unpolarized hippocampal neurons ...[more]

PMID: 16303851

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Project description:BackgroundMelanoma-intrinsic activated β-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS).MethodsWe examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers.ResultsIn the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated β-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases.ConclusionsAPC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

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Neurite outgrowth involves adenomatous polyposis coli protein and beta-catenin.

Publications

Neurite outgrowth involves adenomatous polyposis coli protein and beta-catenin.

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