This web page was produced as an assignment for Genetics 677, an undergraduate course in UW-Madison
GSK3 and Congenital Heart Defect
Introduction to congenital heart defects
According to National Institute of Health [4] each year over 35,000 babies in the United States are born with different forms of congenital heart defects ranging from asymptomatic small defects to life-threatening conditions. The abnormalities can affect (see Figure 1): the heart septum which divides the left from the right ventricle or the one separating the left and right atria; the cardiac valves, located between the major compartments of the heart and which regulate and synchronize the blood flow between these compartments; and they may also have more complex character and affect several structures including the cardiac tissue, blood vessels and others. Depending on the severity of the conditions they may not require any treatment or some routine procedures might be necessary such as catheterization in the site of the defect. In severe cases one or more open heart surgeries may be required.
Figure 1Heart Structure [4]
Congenital heart defects. Retrieved January 31, 2009 from http://www.nhlbi.nih.gov/health/dci/index.html
GSK 3-beta and its role in cardiac morphogenesis
The pathogenesis of these diseases has been studied extensively and in recent years greater attention is placed on the study of genetics and molecular mechanisms which regulate heart development and the key players in these processes. One such factor is a serine/threonine kinase known as GSK3 (glycogen synthase kinase -3). It was initially identified as a kinase that phosphorylates and subsequently inhibits the glycogen synthase[5] but the list of proteins that could be potential substrates for GSK3 expanded throughout the years and has been subject for recent research[1] (Figure 2). The enzyme has two isoforms GSK3-alfa and GSK3-beta[5] (GSK3B) but particular interest has been devoted to the second one -GSK3B which is known to participate in different metabolic processes, neuronal cell development and body pattern formation. GSK3B is part of the Wnt/beta-catenin signaling pathway (see Figure 3) and has been identified as a key regulator in this pathway. Scientists are further trying to determine the specific role the enzyme plays in cell adhesion, cell division, transcription factor activation/deactivation and apoptosis as well as the exact player and pathways involved in its regulation [reviewed by 1]. Lithium for example (which is a GSK3B inhibitor) has been widely used for treatment of bipolar disorder and some studies suggest[6] an increase cases of children born with congenital heart defects from women who received chronic lithium therapy. Although these reports were considered controversial they raised an interesting question – is GSK3 required for normal heart development and where is its place in the regulatory pathway. After detailed experimental research in mice [2,3]scientists suggest that GSK3B is a key regulator in proliferation and differentiation of cardiomyocytes. The purpose of this project is to collect enough information from variety of recourses and provide a critical analysis of some of the questions regarding GSK3B. I hope you enjoy it!
Figure 2 Proposed substrates of GSK3 [1]
Putative substrates are colour-coded according to their proposed function in the cell ; transcription factors (mauve), enzymes that regulate metabolism (blue), proteins bound to microtubules (turquoise),scaffold proteins (orange), or components of the cell division cycle machinery (pink) or involved in cell adhesion (yellow). Transcription factors are subdivided into those that are inhibited (®), activated () or unaffected by the phosphorylation by GSK3. A complex consisting of GSK3, Axin, APC and b-catenin (depicted by ellipses) is critical for regulating embryogenesis. The phosphorylation of cyclin D1 by GSK3, which is thought to occur in the nucleus of the cell, promotes its nuclear export and degradation. Presenilin-1 is reported to act as a scaffold, which facilitates the phosphorylation of tau by GSK3.
Frame, S. (2001).GSK3 takes centre stage more than 20 years after its discovery.The Biochemical journal, 359, 1 -16
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Figure 3 Wnt/beta-catenin pathway [7]
Pathway Description: The Wnt/β-Catenin pathway regulates cell fate decisions during development of vertebrates and invertebrates. The Wnt-ligand is a secreted glycoprotein that binds to Frizzled receptors, which triggers a cascade resulting in displacement of the multifunctional kinase GSK-3β from the APC/Axin/GSK-3 β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral cell-cell adhesion adaptor protein as well as transcriptional co-regulator, is targeted for degradation by the APC/Axin/GSK-3β-complex. Appropriate phosphorylation of β-catenin by coordinated action of CK1 and GSK-3β leads to its ubiquitination and proteasomal degradation through the β-TrCP/SKP complex. In the presence of Wnt binding (On-state), Dishevelled (Dsh) is activated, seemingly at least in part by phosphorylation, which in turn recruits GSK-3β away from the degradation complex. This allows for stabilization of β-catenin levels, nuclear import and recruitment to the LEF/TCF DNA-binding factors where it acts as an activator for transcription by displacement of Groucho-HDAC co-repressors. Additionally, in complex with the homeodomain factor Prop1, β-catenin has also been shown to act in context-dependent activation as well as repression complexes. Importantly, some human cancers harbor point-mutations in β-catenin leading to its deregulated stabilization, and APC as well as axin mutations have also been documented, underscoring the involvement of abnormal activation of this pathway in human tumors. During development the Wnt/β-catenin pathway integrates signals from many other pathways including Retinoic acid, FGF, TGF-β and BMP in many different cell-types and tissues. In addition, the component GSK-3β is also involved in glycogen metabolism and other key pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders.
Wnt/ beta-catenin signaling. Retrieved February 3, 2009 from http://www.cellsignal.com/reference/pathway/Wnt_beta_Catenin.html
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References
1. Frame, S. (2001).GSK3 takes centre stage more than 20 years after its discovery.The Biochemical journal, 359, 1 -16.
2. Kerkela, R. (2008). Deletion of GSK-3 beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. The journal of clinical investigation, 118, iss:11, 3609 -3618
3. Science daily (2008, October 3). Loss of the protein target of lithium disrupts normal mouse embryonic heart development. Retrieved February 1, 2009 from http://www.sciencedaily.com
4. Congenital heart defects. Retrieved January 31, 2009 from http://www.nhlbi.nih.gov/health/dci/index.html
5. National center for biotechnology information http://www.ncbi.nlm.nih.gov/sites
6. Brady, H. and Horgan, J.(1998, January). Lithium and the heart. Chest, 93.1,166-169.
7. Wnt/ beta-catenin signaling. Retrieved February 3, 2009 from http://www.cellsignal.com/reference/pathway/Wnt_beta_Catenin.html
Contact Information
Eva Dimitrova
[email protected]
Page last updated: 04/12/09
