Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.

Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease

Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown. Here we show that presenilin-1 forms a complex with beta-catenin in vivo that increases beta-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize beta-catenin, and lead to increased degradation of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-beta protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer's disease.