From Alzheimer's disease to skin tumors: the catenin connection.

P (PS) 1 and 2 play a key role in the pathogenesis of Alzheimer’s disease (AD) by being essential for the intramembrane cleavage of amyloid precusor protein (APP), thus releasing the pathogenic Ab peptides into the intercellular space (1). Recently, PS1 has been shown to exert an unusual aspartyl protease activity, possibly forming the active center of the g secretase, one of the prime drug targets of an emerging AD therapy (2–4). In addition to the cleavage of APP, the physiological role of which is still not well understood, PS1 is indispensable for several crucial cellular signaling mechanisms mostly operative in tissue development and renewal. The best-studied example for its signaling functions is the proteolytic release of the signal transducing intracellular domain of notch receptors governing cell fate decisions, the inhibition of which causes the severe intrauterine lethal phenotype of PS1deficient mice (5–7). PS1 also negatively regulates the cytoplasmic concentration of b-catenin, a signal integrator of the Wnt pathway. In this issue of PNAS, Xia and colleagues (8) have used a highly elegant means to circumvent prenatal lethality in PS1-deficient mice to analyze the consequences of a PS1 loss of function in adult mice. By reintroducing wild-type PS1 under the control of a Thy1 promoter they have obtained normal levels of expression of PS1 in all tissues but skin keratinocytes. The mice survive up to a normal lifespan, a finding in line with two previous papers (9, 10) using the same approach. Loss of PS1 in keratinocytes is associated with the development of a stereotyped set of skin lesions during adulthood, encompassing multifocal hyperplasia and hyperkeratosis and the formation of epidermal skin tumors, ranging from the benign keratoacanthomas to malignant squamous cell carcinomas. Absence of PS1 expression in keratinocytes was correlated to an increased cytosolic concentration of b-catenin. As a consequence, cyclin D1, one of its target genes involved in cell proliferation control was activated even in normalappearing skin samples. Again fitting into these data, the authors could demonstrate an increased fraction of cells re-entering cell division as a first step in the pathogenesis of the hyperproliferative skin lesions described above. A contribution of impaired notch signaling to the dysregulation of the b-catenin concentration but not to the formation of skin lesions was excluded by the introduction of either wild-type PS1 or a modified version of PS1 still active in notch cleavage but devoid of its b-catenin binding site (PS1 D cat) into PS1-deficient cells in vitro. Thereby, only wild-type PS1 was able to reduce the elevated cytosolic b-catenin to normal values, whereas a similar rescuing effect was not obtained by PS1 D cat, indicating that the notch signaling in these cells did not contribute to the observed phenotype. When discussing the PS1-mediated regulation of b-catenin and the effects of a malfunction of this system, it should be kept in mind that this only reflects one functional aspect of this protein. b-Catenin exists in the cell in two different pools apparently fulfilling distinct functions. The majority of this protein is associated with the cell membrane, where it serves as a molecular bridge between cell adhesion molecules of the cadherin family and the actin cytoskeleton. The second, smaller fraction discussed here is present in the cytosol, where it acts as a signal transducer with the capacity to enter the nucleus, where it combines with DNA binding proteins of the T cell factory lymphoid enhancer factor (TCFyLEF) family to form active transcription factors. This cytosolic concentration of b-catenin is normally kept at a low level by ubiquitination and targeting to the proteasome. The switch to initiate b-catenin degradation is its phosphorylation by glycogen synthase kinase (GSK 3-b). b-catenin phosphorylation in turn is regulated by binding of Wnt proteins to their membrane receptors, which reduces b-catenin phosphorylation and initiates or augments TCFyLEF activ ity (see refs. 10 and 11 for recent reviews of the literature). The functional importance of b-catenin is directly illustrated by the effects of a b-catenin knockout, which terminates mouse development at the onset of gastrulation. Loss of this protein inhibits epithelial cell transdifferentiation and primitive streak formation (12). Conditional knockouts limiting b-catenin deficiency to regions of Wnt expression (13), resulting in severe brain and head malformations, surprisingly also encompassing a loss of cranial neural crest derivatives. Closer to the model investigated here, a pathologic stabilization of cytoplasmic b-catenin concentrations caused by mutations of either b-catenin itself or the catenin-binding proteins axin and adenomatous polyposis coli has been found in several malignancies like hepatoblastoma and adenomatous polyposis coli. Thus, independently or as a part of Wnt-dependent morphogenetic effects ranging from body axis formation to brain development, b-catenin signaling affects cell proliferation control. In skin morphogenesis, b-catenin has been shown to be essential for hair follicle formation, its overexpression causing the ‘‘furry’’ phenotype in mice, but also the development of skin malignancies (14, 15). Analysis of the interaction between PS1 and b-catenin has originally created some confusion because of conflicting reports indicating effects in favor of either a stabilization (16, 17) or a degradation (18, 19) of this protein by PS1. This issue was recently re-evaluated by Soriano et al.