<scp>KIBRA</scp> (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ

Vogt-Eisele, Angela; Krüger, Carola; Duning, Kerstin; Weber, Daniela; Spoelgen, Robert; Pitzer, Claudia; Plaas, Christian; Eisenhardt, Gisela; Meyer, A; Vogt, Gerhard; Krieger, Markus; Handwerker, Eva; Wennmann, Dirk Oliver; Weide, Thomas; Skryabin, Boris V.; Klugmann, Matthias; Pavenstädt, Hermann; Huentelmann, Matthew J.; Kremerskothen, Joachim; Schneider, Armin

doi:10.1111/jnc.12480

Cited by 65 publications

(99 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If no autophosphorylation is assumed, one must make an additional assumption to account for all of the experimental observations above. In this case, simulated ZIP destabilizes aPKC by preventing its binding to a stabilizing protein (Vogt-Eisele et al 2014). In both our model cases, and for values of model parameters consistent with empirical data, bistability and a stimulus-induced switch to persistent high aPKC levels result.…”

Section: [Supplemental Materials Is Available For This Article]supporting

confidence: 58%

“…Additional key assumptions are as follows: Positive feedback at the level of aPKC synthesis is assumed, such that higher levels of aPKC result in higher rates of synthesis (Hernandez et al 2003;Tsokas et al 2005Tsokas et al , 2007Kelly et al 2007;Westmark et al 2010). We also assume that the doubly phosphorylated kinase (K pp ) has a significantly larger dwell time in synapses than does the singly phosphorylated molecule (K p ) (Makuch et al 2011;Li and Gao 2014;Vogt-Eisele et al 2014). K pp is also very stable, as shown in overexpression studies with mutated forms of PKMz with kidney/brain protein (KIBRA), which is primarily located in the synapses (Johannsen et al 2008).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…A major cause of this difference is our empirically plausible assumption (Li and Gao 2014;Vogt-Eisele et al 2014) that the synaptic dwell time of the doubly phosphorylated protein is much higher than that of the singly phosphorylated protein (t pp ≫ t p ). Similar to empirical studies, eliminating synthesis in the model (a ¼ g 0, PSI) prevents the induction of L-LTP ( Fig.…”

Section: Model Description and Simulated Bistability In Apkc Levelmentioning

confidence: 99%

“…For the model variant in which the turn site was phosphorylated by an external kinase (Supplemental Fig. S4), ZIP (g 0 and t pp t p ) can also destabilize doubly phosphorylated kinase by preventing it from binding to a protective protein such as KIBRA (Vogt-Eisele et al 2014). In either case, it is sufficient to apply ZIP on the order of t p (much shorter than t pp ) in order to reverse L-LTP by the kinase inhibitor (Supplemental Fig.…”

Section: Model Description and Simulated Bistability In Apkc Levelmentioning

confidence: 99%

See 3 more Smart Citations

Atypical PKCs in memory maintenance: the roles of feedback and redundancy

Jalil¹,

Sacktor

Shouval³

2015

Learn. Mem.

View full text Add to dashboard Cite

Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMz and PKCi/l, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated.

show abstract

Section: [Supplemental Materials Is Available For This Article]supporting

confidence: 58%

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Section: Model Description and Simulated Bistability In Apkc Levelmentioning

confidence: 99%

Section: Model Description and Simulated Bistability In Apkc Levelmentioning

confidence: 99%

See 2 more Smart Citations

Atypical PKCs in memory maintenance: the roles of feedback and redundancy

Jalil¹,

Sacktor

Shouval³

2015

Learn. Mem.

View full text Add to dashboard Cite

show abstract

“…Vogt-Eisele et al (8) replicated the coexpression of KIBRA and PKMζ and showed that KIBRA is necessary to prevent PKMζ degradation. KIBRA ablation was associated with reduced hippocampal PKMζ levels and diminished memory performance.…”

mentioning

confidence: 99%

Response to: Further Support for an Association between the Memory-Related Gene WWC1 and Posttraumatic Stress Disorder: Results from the Detroit Neighborhood Health Study

Wilker

Elbert

Papassotiropoulos

et al. 2014

Biological Psychiatry

View full text Add to dashboard Cite

P osttraumatic stress disorder (PTSD) is characterized by pathologic, intrusive memories of the experienced traumata. The risk to develop PTSD depends on the cumulative exposure to traumatic experience (traumatic load), on the extent of childhood adversities, and on genetic factors. The latter account for about one third of interindividual variability (1). Despite this pronounced genetic influence, little is known about the underlying genetic factors and molecular processes. Considering the strong role of fear memory development in PTSD, we recently argued for the investigation of memory-related genes in PTSD (2,3). Candidate gene association studies allow for such theorydriven analyses; however, they require replication to identify reliable associations between molecular genetic factors and PTSD.The gene encoding the protein KIBRA (WWC1) is reliably associated with human episodic memory (4,5) and accumulating evidence from three independent samples now suggests a role of this gene in PTSD etiology. We discovered that WWC1 genotype influenced PTSD risk in a sample of Rwandan genocide survivors and replicated this finding in a second study with survivors of the rebel war in Northern Uganda (6). Minor-allele carrier status of two WWC1 single nucleotide polymorphisms (SNPs) (rs10038727 and rs4576167) was associated with decreased risk for lifetime PTSD development, an effect that held true for all levels of traumatic load. Our results on rs10038727 were replicated by Sumner et al. (7), who examined a large, predominantly African American sample from the Detroit Neighborhood Health Study. The authors also included a measure of lifetime trauma exposure and found a strong main effect of trauma. However, neither in this study nor in our study was a gene Â environment (traumatic load) interaction effect observed.The accumulating evidence for the relevance of WWC1 genotype for both human memory and memory-related psychopathology brings up several research questions.

show abstract

WW and C2 domain–containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway

et al. 2018

Self Cite

View full text Add to dashboard Cite

The Hippo pathway regulates cell differentiation, proliferation, and apoptosis. Upon activation, it inhibits the import of the transcriptional coactivator yes‐associated protein (YAP) into the nucleus, thus suppressing transcription of pro‐proliferative genes. Hence, dynamic and precise control of the Hippo pathway is crucial for organ size control and the prevention of tumor formation. Hippo signaling is controlled by a growing number of upstream regulators, including WW and C2 domain–containing (WWC) proteins, which trigger a serine/threonine kinase pathway. One component of this is the large tumor suppressor (LATS) kinase, which phosphorylates YAP, trapping it in the cytoplasm. WWC proteins have been shown to interact with LATS in vitro and stimulate its kinase activity, thus directly promoting cytoplasmic accumulation of phosphorylated YAP. However, the function of the WWC proteins in the regulation of cell proliferation, organ size control, and tumor prevention in vivo has not yet been determined. Here, we show that loss of hepatic WWC expression in mice leads to tissue overgrowth, inflammation, fibrosis, and formation of liver carcinoma. WWC‐deficient mouse livers display reduced LATS activity, increased YAP‐mediated gene transcription, and enhanced proliferation of hepatic progenitor cells. In addition, loss of WWC expression in the liver accelerates the turnover of angiomotin proteins, which act as negative regulators of YAP activity. Conclusion: Our data define an essential in vivo function for WWC proteins as regulators of canonical and noncanonical Hippo signaling in hepatic cell growth and liver tumorigenesis. Thus, expression of WWC proteins may serve as novel prognostic factors in human liver carcinoma. (Hepatology 2018;67:1546‐1559)

show abstract

KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ

Cited by 65 publications

References 37 publications

Atypical PKCs in memory maintenance: the roles of feedback and redundancy

Atypical PKCs in memory maintenance: the roles of feedback and redundancy

Response to: Further Support for an Association between the Memory-Related Gene WWC1 and Posttraumatic Stress Disorder: Results from the Detroit Neighborhood Health Study

WW and C2 domain–containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway

Contact Info

Product

Resources

About