Presenilin Couples the Paired Phosphorylation of β-Catenin Independent of Axin Implications for β-Catenin Activation in Tumorigenesis

The Alzheimer's disease-linked gene presenilin 1 (PS1) is required for intramembrane proteolysis of APP and Notch. In addition, recent observations strongly implicate PS1 as a negative regulator of the Wnt/beta-catenin signaling pathway, although the mechanism underlying this activity is unknown. 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. Thus, presenilin deficiency results in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.

[1]  M. Peifer,et al.  A screen for mutations that suppress the phenotype of Drosophila armadillo, the beta-catenin homolog. , 2000, Genetics.

[2]  S. Tonegawa,et al.  Skeletal and CNS Defects in Presenilin-1-Deficient Mice , 1997, Cell.

[3]  A. Ben-Ze'ev,et al.  The Integration of Cell Adhesion with Gene Expression: The Role of β-Catenin , 2000 .

[4]  K. Davis,et al.  Neurofibrillary tangles, Alzheimer's disease, and Lewy bodies , 1990, The Lancet.

[5]  Hideki Yamamoto,et al.  Phosphorylation of Axin, a Wnt Signal Negative Regulator, by Glycogen Synthase Kinase-3β Regulates Its Stability* , 1999, The Journal of Biological Chemistry.

[6]  M. Frosch,et al.  Presenilin 1 Facilitates the Constitutive Turnover of β-Catenin: Differential Activity of Alzheimer’s Disease–Linked PS1 Mutants in the β-Catenin–Signaling Pathway , 1999, The Journal of Neuroscience.

[7]  Fumiaki Ito,et al.  Cytoskeletal reorganization by soluble Wnt‐3a protein signalling , 1998, Genes to cells : devoted to molecular & cellular mechanisms.

[8]  D. Borchelt,et al.  Protein Topology of Presenilin 1 , 1996, Neuron.

[9]  R. Moon,et al.  The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. , 1996, Genes & development.

[10]  J. Rommens,et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene , 1995, Nature.

[11]  Xi He,et al.  Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism , 2002, Cell.

[12]  E. Masliah,et al.  alpha-Synuclein is phosphorylated in synucleinopathy lesions. , 2002, Nature cell biology.

[13]  S. Orsulic,et al.  Negative regulation of Armadillo, a Wingless effector in Drosophila. , 1997, Development.

[14]  Iva Greenwald,et al.  Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene , 1995, Nature.

[15]  K. Mostov,et al.  NH2-terminal Deletion of β-Catenin Results in Stable Colocalization of Mutant β-Catenin with Adenomatous Polyposis Coli Protein and Altered MDCK Cell Adhesion , 1997, The Journal of cell biology.

[16]  A. Goate,et al.  A common enzyme connects notch signaling and Alzheimer's disease. , 2000, Genes & development.

[17]  P. Polakis.  Wnt signaling and cancer. , 2000, Genes & development.

[18]  E. Masliah,et al.  α-Synuclein is phosphorylated in synucleinopathy lesions , 2002, Nature Cell Biology.

[19]  R. Krumlauf,et al.  Evidence for a mitogenic effect of Wnt-1 in the developing mammalian central nervous system. , 1994, Development.

[20]  S. Neo,et al.  Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels. , 2000, Biochemical and biophysical research communications.

[21]  K. Imahori,et al.  Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. , 1992, The Journal of biological chemistry.

[22]  Matthias Mann,et al.  Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. , 2002, Genes & development.

[23]  P. Greengard,et al.  Evidence for phosphorylation and oligomeric assembly of presenilin 1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Nadin,et al.  Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. , 2000, Nature.

[25]  Laurence H. Pearl,et al.  Crystal Structure of Glycogen Synthase Kinase 3β Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition , 2001, Cell.

[26]  Jörg Stappert,et al.  β‐catenin is a target for the ubiquitin–proteasome pathway , 1997 .

[27]  Hui Zheng,et al.  Presenilin 1 Negatively Regulates β-Catenin/T Cell Factor/Lymphoid Enhancer Factor-1 Signaling Independently of β-Amyloid Precursor Protein and Notch Processing , 2001, The Journal of cell biology.

[28]  Hui Zheng,et al.  Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  D. Selkoe,et al.  Subcellular Distribution and Turnover of Presenilins in Transfected Cells* , 1998, The Journal of Biological Chemistry.

[30]  Yusuke Nakamura,et al.  AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1 , 2000, Nature Genetics.

[31]  D. Price,et al.  Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm , 1997, Nature.

[32]  G. Jicha,et al.  cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease , 1999, The Journal of Neuroscience.

[33]  C. Haass,et al.  Proteolytic fragments of the Alzheimer's disease associated presenilins-1 and -2 are phosphorylated in vivo by distinct cellular mechanisms. , 1998, Biochemistry.

[34]  D. Kalderon,et al.  Proteolysis of the Hedgehog Signaling Effector Cubitus interruptus Requires Phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1 , 2002, Cell.

[35]  P. Roach,et al.  A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. , 1994, The Journal of biological chemistry.

[36]  Wim Annaert,et al.  Where Notch and WNT Signaling Meet , 2001, The Journal of cell biology.

[37]  Min Xu,et al.  Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 , 2000, Nature.

[38]  Andrew P McMahon,et al.  A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. , 2002, Development.

[39]  P. Fraser,et al.  The Presenilin 1 Protein Is a Component of a High Molecular Weight Intracellular Complex That Contains β-Catenin* , 1998, The Journal of Biological Chemistry.

[40]  B. Strooper,et al.  Presenilins and the intramembrane proteolysis of proteins: facts and fiction , 2001, Nature Cell Biology.

[41]  K. Kosik.  A partnership that delivers , 1999, Nature Medicine.

[42]  Akira Kikuchi,et al.  Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK‐3β and β‐catenin and promotes GSK‐3β‐dependent phosphorylation of β‐catenin , 1998 .

[43]  M. Fortini,et al.  Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants , 1999, Nature.

[44]  B. Strooper,et al.  Total inactivation of γ–secretase activity in presenilin-deficient embryonic stem cells , 2000, Nature Cell Biology.

[45]  N. Perrimon,et al.  Presenilin Affects Arm/β-Catenin Localization and Function in Drosophila , 2000 .

[46]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[47]  P. Burger,et al.  Nuclear Localization and Mutation of β‐Catenin in Medulloblastomas , 2000 .

[48]  U. Lendahl,et al.  Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development , 1996, Mechanisms of Development.

[49]  P. Roach,et al.  Ordered multisite protein phosphorylation. Analysis of glycogen synthase kinase 3 action using model peptide substrates. , 1990, The Journal of biological chemistry.

[50]  E. Fuchs,et al.  De Novo Hair Follicle Morphogenesis and Hair Tumors in Mice Expressing a Truncated β-Catenin in Skin , 1998, Cell.

[51]  A. Levey,et al.  Presenilin 1 Independently Regulates β-Catenin Stability and Transcriptional Activity* , 2001, The Journal of Biological Chemistry.

[52]  M. Peifer,et al.  Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. , 2000, Science.