Beta-Catenin and PS1
Chris Weihl, with Bruce Yankner, Benjamin Wolozin, Eddie Koo, and Kenneth Kosik led this live discussion on 13 August 1999. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 31 August 2006
By Chris Weihl
Originally cloned and identified in late 1995, mutations
in presenilin-1 (PS1) and presenilin-2 (PS2) lead to
an aggressive and early onset form of familial Alzheimer's
disease (AD). To date >50 familial AD causing missense
mutations have been identified in the presenilins. The
putative structure and localization of the presenilins
is presumed to be an 8 transmembrane domain, endoplasmic
reticulum(ER)/golgi membrane resident protein with a
large hydrophilic loop exposed to the cytosol (reviewed
in Price, 1998).
Despite intense efforts over the past 4 years, the function of the presenilins
remain unclear. Early data suggested the presenilins play a key role in
development, since they are functionally homologous to a C. elegans protein,
SEL-12, involved in Notch signal transduction. Moreover, PS1 knockout embryos
demonstrate embryonic lethality and developmental disruptions reminiscent
of Notch knockout mice (e.g. defects in somite segmentation). Notch signaling
involves the transduction of a developmental signal from one cell via the
surface ligand, Delta/Serrate, and its subsequent binding to the Notch receptor
on an adjacent cell. Intracellularly-associated Notch then releases from
the cell membrane and enters the nucleus turning on a specific developmental
The pathological consequences of the PS1 mutations may involve an increase
in the misprocessing of the amyloid precursor protein, APP, resulting in
the secretion of the more amyloidogenic Aβ1-42 peptide and enhancing
amyloid plaque formation in FAD patients. This may be due to PS1's role
in protein trafficking and perhaps its "proposed" secretase function.
Others have suggested that mutations in PS1 enhance neuronal susceptibility
Very recent data has emerged suggesting that PS1 plays a role in another
developmental signaling pathway, Wingless, via PS1's binding to beta-catenin.
This association has the potential of elucidating PS1's role in development
and Notch signaling (as wingless and notch pathways may interact). In addition,
FAD mutations in PS1 may disregulate beta-catenin signaling, thereby potentiating
neuronal apoptosis. Finally, while evidence exists suggesting PS1's role
in Aβ deposition, PS1's association with beta-catenin and its regulatory
kinase, GSK-3 beta, (also known as tau protein kinase-1) link PS1 to the
hyperphosphorylation of tau and neurofibrillary tangle formation(NTF).
PS1 Associates with Armadillo Repeat
Several studies have been aimed at identifying proteins
that interact with the presenilins. Initial evidence
suggested that PS1 associates with APP; however some
papers disagree with this finding. In order to screen
for proteins that might interact with PS1, Zhou and
colleagues used the hydrophilic loop domain of PS1 as
bait in a yeast-two hybrid screen. Yeast two hybrid
studies express one protein fused to the DNA binding
domain of a transcription factor (GAL4) as "bait"
and screen a cDNA library with fused sequences to the
GAL4 transactivation domain. Positive interactions are
assayed by the ability of "bait" and "prey"
to associate and lead to the expression of a reporter
protein (beta-galactosidase). This screening strategy
identified a novel armadillo repeat protein, delta-catenin,
that was highly expressed in brain. Subsequent studies
identified that PS1 could also associate with a delta-catenin
homologue, beta-catenin in HEK293 cells (Zhou, et al.,
Since this study, PS1 has been shown to associate and colocalize with several
other armadillo repeat proteins including beta-catenin, delta-catenin (also
termed NPRAP) and p0071 but not to associate with alpha-catenin or gamma-catenin
(Levesque, et al. 1999; Stahl, et al., 1999). The interaction has been mapped
to the C-terminal hydrophilic loop domain of PS1 (a.a. 263-407). In addition,
the PS1:beta-catenin association is abrogated upon caspase mediated cleavage
of PS1 (at a.a. 329 and 341) during apoptosis (Tesco, et al., 1998). FAD
mutations in PS1 do not appear to disrupt the association of PS1 with beta-catenin,
delta-catenin or p0071. The loop domain of PS2 has been reported to associate
with beta-catenin (Levesque, et al., 1999); however several reports fail
to see this interaction.
What Are Beta-catenin and Armadillo
An armadillo repeat is a 42 amino acid motif involved
in protein-protein association and is found in proteins,
such as beta-catenin. Armadillo repeat proteins are
a growing class of diverse signaling proteins involved
in cell to cell adhesion, protein-protein interactions
and signal transduction. Mutations in some armadillo
repeat proteins lead to distinct pathologies ranging
from cancer to neurodegeneration (reviews include Dale,
1998; Willert and Russe, 1998; Barth, et al., 1997).
The best-characterized armadillo repeat protein is beta-catenin. Beta-catenin
is a component of the WNT signaling pathway of early development. WNT signaling
allows for cell to cell communication during important developmental decisions
such as cell-fate determination and vertebrate CNS pattern formation. The
pathway of WNT signaling in a developing neuron is as follows:  a secreted
or cell associated WNT ligand binds to an adjacent cells Frz receptor. 
Frz activation transduces a signal to inactivate the serine/threonine kinase
GSK-3 beta via an unidentified pathway mediated by another protein, Disheveled.
 GSK-3 beta is responsible for regulating the stability of beta-catenin.
When GSK-3 beta is active it phosphorylates beta-catenin at multiple sites
targeting beta-catenin for ubiquitination and proteasomal degradation. When
GSK-3 beta is inactivated (as in WNT signaling), beta-catenin is stabilized.
 unphosphorylated and stable beta-catenin can then enter the nucleus
where it co-activates the Tcf/LEF family of transcription factors setting
the cell on its programmed developmental path of gene expression.
In the absence of WNT ligands and Frz receptors after development, the role
of beta-catenin in cell signaling is more unclear. One potential role involves
trophic factor stabilization of beta-catenin. After development, growth
factor stimulation can activate the PI3 kinase/Akt survival pathway. Akt
is serine/threonine kinase that inactivates GSK-3 beta resulting in stabilized
beta-catenin. The role of beta-catenin in cell survival remains unclear.
However, it is known that point mutations that change the serine/threonine
regulatory residues in beta-catenin increase its stability and lead to some
forms of cancer. In addition, the tumor suppressor, APC (adenomatous polyposis
coli) and another protein, axin, tether beta-catenin to GSK-3 beta, enhancing
GSK-3 beta mediated phosphorylation of beta-catenin and decreasing beta-catenin
Mutations in or Deletion of APC Results
in an Increased Stability of Beta-catenin and Tumor
Another role of beta-catenin and perhaps its homologues,
delta-catenin and p0071, involves cell to cell adhesion
by their association with cadherins. Cadherins are a
large family of cell adhesion molecules involved in
cell to cell interactions at sites known as desmosomes
and adherins junctions. Beta-catenin associates with
the cytoplasmic domains of E-cadherin and alpha catenin
linking them to the actin cytoskeleton. Tyrosine phosphorylation
of beta-catenin during cell migration or neuronal process
formation releases beta-catenin from E-cadherin and
the cytoskeleton allowing for a change in cell morphology
or cell adhesion. This role is distinct from beta-catenin's
role in signal transduction, as beta-catenin mutants
can be generated to disrupt gene expression but not
alter its ability to bind E-cadherin and alpha catenin.
It has been suggested that beta-catenin's role in both
cell adhesion and signal transduction may be mediated
through APC since it competes with E-cadherin at the
same site on beta-catenin.
Role of PS1 in Beta-catenin Metabolism
Several studies demonstrate that PS1 associates with
beta-catenin in vivo. However, the function of this
interaction is unknown. Recently, four papers from independent
groups have shown that PS1, in addition to binding with
beta-catenin, plays a role in regulating beta-catenin
metabolism and FAD mutations in PS1 may perturb this
regulation. Unfortunately, these papers use a wide range
of differing techniques and show conflicting results
regarding the effects of PS1 on the "stability"
beta-catenin. We intend to review the theoretical, as
well as technical differences in these recent reports.
Hence, the focus of this discussion is intended to highlight
the "putative roles" that PS1 and FAD mutations
may have on beta-catenin's function.
Zhang and colleagues demonstrated that when PS1-WT and myc-tagged beta-catenin
were co-expressed in HEK293 cells, myc-tagged beta-catenin showed an increase
in stability. On the contrary, FAD mutations in PS1, when co-expressed with
beta-catenin, failed to enhance beta-catenin stability. Moreover, transgenic
mice expressing mutant PS1 showed an increase in beta-catenin immunoreactive
degradation products, suggesting a decrease in beta-catenin stability. PS1-deficient
fibroblast cultures also had an increase in beta-catenin degradative products.
Finally, brain homogenates from FAD patients with PS1 mutations showed a
significant reduction in the levels of beta-catenin.
A report by Murayama and colleagues demonstrated a somewhat different set
of results. Transient transfection of PS1-WT and mutant PS1 caused a dramatic
decrease in the levels of "cytoplasmic" endogenous beta-catenin.
In addition, using a sensitive reporter assay for beta-catenin function,
Murayama and colleagues further demonstrated that beta-catenin stability
was decreased significantly more in PS1 mutant expressing cells. The reporter
assay measured the amount of beta-catenin that is able to transactivate
a Tcf/LEF promoter upstream of a luciferase reporter gene. This technique
assesses beta-catenin function, stability and its entry into the nucleus.
Nishimura and colleagues assayed the effect of PS1 on beta-catenin function
by directly immunostaining human FAD patient-derived fibroblasts for nuclear
localized beta-catenin. By inhibiting GSK-3 beta (the regulatory kinase
of beta-catenin) and thus increasing the stability of beta-catenin, they
assayed the amount of beta-catenin that was translocated into the nucleus.
FAD patient fibroblasts with PS1 mutations had a significantly reduced amount
of nuclear localized beta-catenin. In addition, one cell line with a PS2
mutation showed a similar result. Nishimura and colleagues propose that
this phenomenon is not due to a decrease in beta-catenin stability but instead
suggest that mutant PS1 affects the trafficking beta-catenin from the cytoplasm
to the nucleus. The basis for these observations results from experiments
looking at the stability of beta-catenin in these cells following GSK-3
beta inhibition and proteasomal inhibition.
Kang and colleagues show different results in regard to PS1's function upon
beta-catenin stability. They demonstrate that PS1-WT expression in HEK293
cells decreases the stability of endogenous beta-catenin, whereas FAD mutant
PS1 increases the stability of beta-catenin as compared with untreated controls.
Moreover, FAD PS1 transgenic mice demonstrate an increase in beta-catenin
levels that correlates with PS1-mutant expression levels. Finally, PS1-deficient
fibroblast show an increase in the stability of beta-catenin as compared
with normal fibroblasts.
Kang and colleagues lend more insight into the role of PS1 in beta-catenin
metabolism by confirming a previous study by Takashima and colleagues who
demonstrated that PS1-WT associates with GSK-3 beta in addition to beta-catenin.
In contrast to Takashima who demonstrated an increase in GSK-3 beta binding
to mutant PS1, Kang and colleagues failed to find an association between
GSK-3 beta and mutant PS1.
These reports are in agreement that PS1 associates with
beta-catenin, and that PS1-WT and FAD mutants affect
the metabolism of beta-catenin. However, it is still
unclear from these papers whether, PS1 and FAD PS1 mutants
positively or negatively regulate beta-catenin (see
Table). One problem is the diverse range of techniques
presented in these papers to assess beta-catenin activity.
Zhang et al pulse-labeled transfected beta-catenin from
PS1 expressing cells and observed beta-catenin degradative
products in brain homogenates. Murayama et al measured
the levels of cytosolic endogenous beta-catenin and
assayed beta-catenin's ability to activate a reporter
construct. Nishimura et al calculated the number of
beta-catenin positive nuclei to assess beta-catenin
functionality. Finally, Kang et al pulse labeled total
endogenous beta-catenin in order to arrive at their
conclusions. Before any conclusions can be made regarding
PS1's function, one must take into to account the varied
methods of experimentation.
Beta-catenin stability and/or entry into the nucleus compared
Questions for the Panel
1) What is your current model of how PS1 and FAD PS1 mutants affect beta-catenin
function? How do resolve your model in light of the differences seen by
Reply by Eddie Koo: We have no updates to our model as to how PS1 affect beta-catenin beyond what’s proposed in our paper, i.e. PS1 may be a scaffold whereby beta-catenin and GSK may complex to. We also discussed in that article possible explanations to differences in results with the other published articles. The difficulty, as was pointed out in the terrific summary of Chris Weihl, is that the assays were very different. So if we all did the experiments the same way and expressed the same mutations, maybe the differences will disappear. One concern that I have is how reliable are the results obtained from transient transfections. For example, in transients, there is a high expression of full length PS that rarely exists normally. Supposing that the N- and C-terminal fragments are the active molecules, then those are not really increased that much and the full length molecules can give misleading results.
Reply by Bruce Yankner: Our model is based on evidence that a cytoplasmic complex of axin with beta catenin, GSK3 and APC mediates the phosphorylation and degradation of beta catenin. Our results are consistent with the formation of an alternative PS1-beta catenin complex that inhibits catenin phosphorylation thereby increasing catenin stability. This complex would also faciliteate beta catenin
translocation to the nucleus, possibly by promoting the interaction of beta catenin with the Lef-1/Tcf family of transcription factors. It is also possible that PS1 complex formation with GSK3 inhibits the ability of this kinase to phosphorylated beta catenin, which would also result in increased catenin stability. Our results suggest that FAD PS1 mutations reduce the ability of PS1 to stabilize beta catenin, increasing catenin degradation and reducing catenin signaling.
The disparate results on the effect of PS1 on beta catenin stability from several groups most likely reflect technical issues inherent in the experiments. Everyone agrees that PS1 complexes with
beta catenin; the point of contention is the functional consequence of complex formation. There are
several key technical issues that may account for the disparities, which will hopefully be addressed in the upcoming forum. One central issue is the use of SV40-transformed fibroblasts from PS1-null mice. At the Keystone meeting, I presented results from my lab which show that SV40 transformation downregulates PS1, and that this may occur through the induction of p53 by SV40. We found no significant difference in steady state catenin levels or degradation products in SV40-transformed
fibroblasts from PS1-KO and wild-type mice. By contrast, non-transformed fibroblast cultures obtained Jie Shen's and Bart DeStrooper's PS1-KO animals showed increased beta catenin degradation. Moreover, several groups have recently informed me that they have been unable to obtain good expression levels of exogenous PS1 in SV40-transformed PS1-KO fibroblasts. Thus, results from these cells, which have been used in some studies, may be problematic.
A key piece of information which has not yet been published is the effect of PS1 on the biological activity of beta catenin in vivo. This information could provide some clarity by bypassing the
confounding technical issues in the in vitro experiments. Our group and another group now have reults which suggest that PS1 can potentiate beta catenin signaling in vivo in Drosophila and Xenopus, findings
which have not yet been published. These results are consistent with a stabilizing effect of PS1 on beta catenin.
2) Do changes in beta-catenin stability/function contribute to FAD? Saura
and colleagues demonstrated that deletion of the PS1 loop region associated
with beta-catenin binding is not necessary for the phenotypic changes in
Aβ production seen in all FAD mutants (Saura, et al., and personal communication with Drs. Saura and Thinakaran).
Reply by Eddie Koo: There is as yet no evidence that changes in beta-catenin stability/function contribute to FAD that I’m aware of. There is really only the apoptosis study of Bruce Yanker that relate to possible AD pathogenesis. But his experimental outcome may not be a direct consequence of changes in catenin stability. I am not aware of anyone having any direct evidence linking this pathway to AD pathophysiology. I am discounting the GSK/tau connection for the moment. Whether the catenin stability, catenin translocation, etc. directly influences AD pathology is up in the air. For that matter, there is no data that Notch signaling has any bearing on AD pathophysiology either. Maybe we will hear differently on Friday.
I would explain Gopal’s data this way: the loop may not be the only site where catenin interacts with PS1. One of the difficulty in attributing PS1 to AD pathogenesis is what to do with PS2. If we assume they play a similar role, then PS2 also ought to interact with catenins. Since the loop is so different, perhaps there are other sites of interaction between PS and catenin. Alternatively, PS may interact with other partners that in turn influence catenin. Remember that any direct association by 2-hybrid assay has only been shown with PS1 loop and delta-catenin and p0071. The evidence linking PS1 to catenin in a
complex is only by co-IP. Whether there is another binding partner in the complex remains unknown. Peter Hyslop’s paper showed that PS1-catenin complex appears to migrate heavier than the sum of the
molecular weights, assuming 1:1 stoichometry and no dimerization. Finally, I would mention a recent paper for which Bruce is a co-author. This deals with the beta-trp F box protein that also modulates beta catenin degradation. So there are certainly other potential binding partners that have not been reported.
Reply by Bruce Yankner: Although several studies suggest that FAD PS1 mutations alter beta catenin
stability or nuclear translocation, the case for a role of beta catenin in the pathogenesis of FAD is not yet compelling. The unpublished results of Saura and colleagues suggest that the PS1-catenin
interaction may not be involved in the elevation of Aβ42 production by FAD PS1 mutations. However, it has not been established that this is the mechanism by which PS1 mutations cause FAD. Although a
substantial body of evidence suggests that Aβ42 is involved in AD pathogenesis, a role for increased neuronal vulnerability to apoptosis must also be considered, as suggested by the work of Ben Wolozin and
Mark Mattson and colleagues on PS1 mutations. Our recently published findings suggest that PS1 mutations could increase neuronal vulnerability to apoptosis by impairing beta catenin signaling (Zhang
et al., 1998). However, the in vivo relevance of this mechanism remains to be established.
3) Does PS1's role in beta-catenin metabolism explain the presence of
hyperphosphorylated tau and neurofibrillary tangle formation in FAD patients?
Conflicting reports suggests that mutant PS1 affects the activity of GSK-3
beta (Takashima, et al. 1998; Nishimura, et al. 1999; Irving and Miller,
Reply by Eddie Koo: We have not looked at tau phosphorylation. However, I find it hard to believe that the small changes we see with PS1 mutations can have a big influence on GSK activity. The percentage of GSK that is actually bound to PS is very small.
Reply by Bruce Yankner: The role of PS1 in neurofibrillary tangle (NFT) formation in FAD is at present unclear. Our group and others have demonstrated PS1 colocalization with a subset of NFTs in AD. Takashima et al. and Kang et al. report that PS1 complexes with GSK3, and Takashima et al. find that FAD PS1 mutations increase tau phoshorylation. However, other groups have not detected an effect on
tau phosphorylation. An important difference between the Takashima report and the others is that Takashima evaluated the effect of PS1 mutations on tau phosphorylation by endogenous kinases, whereas the other groups utilized GSK3 overexpression systems which could potentially swamp out a PS1 effect (Irving and Miller, 1997; Nishimura et al., 1999). None of the groups have yet examined this issue in a neuronal system. I believe that the best approach would be to analyze endogenous tau phosphorylation in PS1 wt and mutant transgenic and knock-in mice.
4) Does PS1's role in beta-catenin metabolism explain the developmental
phenotype seen in PS1 knockout embryos? Recent data suggest that the wingless
pathway may interact and negatively regulate Notch signaling.
Reply by Eddie Koo: Our hypothesis is that PS1 role’s in beta catenin metabolism underlies some (unknown) aspect of the developmental phenotype seen in PS1 KO animals. On the other hand, the evidence is certainly against a major role for catenin at this time. This is because the notch results are quite impressive. Having said that, Chris is absolutely correct to point out that there is a lot of cross-talk
between the notch and catenin/armadillo pathways, or signaling network. So in a roundabout way, disturbances in catenin function may ultimately influence notch function.
Reply by Bruce Yankner: The developmental phenotype in PS1-KO mice has been largely attributed to impaired Notch signaling, but it is unclear whether this is the only contributory signaling pathway. The impaired development of the paraxial mesoderm in PS1-KO mice is consistent with loss of Notch signaling. However, loss of Wnt signaling can also affect paraxial mesoderm development (Yoshikawa et al., 1997, Dev. Biol. 183:234). Morevoer, the reduced number of neural progenitors in PS1-KO mice reported by Shen and Tonegawa could also be consistent with impaired Wnt signaling (Ikaya et al., 1997, Nature 389:966). I do not believe that the developmental phenotype of PS1-KO mice will be entirely due to Notch. For example, Paul Saftig has recently described a cortical migration defect in PS1-KO mice which is not a known Notch-related phenotype.
5) Expand on the significance of PS1 interactions with other armadillo
repeat proteins (e.g. delta-catenin and p0071). Will these interactions
be more important to FAD pathogenesis since they are expressed neuronally
instead of ubiquitously like beta-catenin?
Reply by Eddie Koo: So little is known about the other catenins that it is hard to even guess where the other catenins come in. These other catenins may appear to interact with PS only in our artefactual systems because of the presence of the armadillo repeats. On the other hand, if the other catenins were to play a role, then it is likely not through signaling because they have rather low signaling activity, at least through the known pathways. In which case, what’s left are the cadherin
Reply by Bruce Yankner: There is not enough information about PS1 interactions with other armadillo proteins in the context of FAD to address this question. The point that beta catenin is ubiquitously expressed whereas delta catenin is neuron-specific, while interesting, does not address the role of these proteins in AD. APP and presenilins are ubiquitously expressed, yet these proteins can still give rise to brain-specific pathology in AD.
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