GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization

Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
Current drug targets (Impact Factor: 3.02). 12/2006; 7(11):1411-9. DOI: 10.2174/1389450110607011411
Source: PubMed


GSK3 is a multifunctional protein kinase that is pivotal for the regulation of metabolism, the cytoskeleton, and gene expression. Multicellular eukaryotes utilize GSK3 as a molecular switch to specify distinct cell fates, but also to organize these cells spatially within the developing organism. We discuss the central role of GSK3 in control of the Wnt, Hedgehog, cAMP (in Dictyostelium), and other signaling pathways, but also focus on significant new evidence that GSK3 is required to establish cell polarity.

Download full-text


Available from: Leung Kim
  • Source
    • "It interacts with a conserved motif on the Gli protein, and enables Gli phosphorylation by PKA, GSK3β and CK1 [12]. GSK3β is a multifunctional serine/threonine kinase involved in metabolic and developmental pathways, and many cellular functions such as stem cell differentiation, self-renewal and apoptosis [13]. The role of GSK3β in the Hh-Gli signaling pathway is twofold: phosphorylation of Gli proteins, tagging them for degradation and processing into repressor forms in the inactive state, or binding SuFu in ligand-stimulated cells and enabling the release of Gli from the complex [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of Hedgehog-Gli (Hh-Gli) signaling in colon cancer tumorigenesis has not yet been completely elucidated. Here we provide strong evidence of Hh-Gli signaling involvement in survival of colon cancer cells, with the main trigger of activation being deregulated GSK3β. Our clinical data reveals high expression levels of GSK3β and Gli3 in human colon cancer tissue samples, with positive correlation between GSK3β expression and DUKES' stage. Further experiments on colon cancer cell lines have shown that a deregulated GSK3β upregulates Hh-Gli signaling and positively affects colon cancer cell survival. We show that inhibition of GSK3β with lithium chloride enhances Gli3 processing into its repressor form, consequently downregulating Hh-Gli signaling, reducing cell proliferation and inducing cell death. Analysis of the molecular mechanisms revealed that lithium chloride enhances Gli3-SuFu-GSK3β complex formation leading to more efficient Gli3 cleavage and Hh-Gli signaling downregulation. This work proposes that activation of the Hh-Gli signaling pathway in colon cancer cells occurs non-canonically via deregulated GSK3β. Gli3 seems to be the main pathway effector, highlighting the activator potential of this transcription factor, which is highly dependent on GSK3β function and fine tuning of the Gli3-SuFu-GSK3β platform.
    Full-text · Article · Sep 2015 · Biochimica et Biophysica Acta
  • Source
    • "Glycogen synthase kinase 3β (GSK3β) is a ubiquitously expressed constitutively active serine/threonine kinase that regulates multiple signaling pathways, thereby controlling a broad spectrum of cellular responses, including metabolism, gene transcription, protein translation, cell-cycle regulation, and apoptosis [35]. In particular, inhibition of GSK3β causes the upregulation of the transcriptional regulators Sp1, SNAIL, and SMAD [25], [27], [36]. Recent evidence suggests that the gene for CAR, CXADR, is regulated by Sp1, SNAIL, and SMAD [37]–[39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR) is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR.
    Full-text · Article · Nov 2012 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The protein tyrosine phosphatase (PTP) superfamily of enzymes functions with protein tyrosine kinases to regulate a broad spectrum of fundamental physiological processes. Addition of the PTP inhibitor potassium bisperoxo(1,10-phenanthroline)oxo-vanadate(V) [bpV(phen)] to the culture medium of human ovarian cancer cells (OVCAR-3) resulted in a dose-dependent decrease in the formation of tumors in a 3-D culture system. An evaluation of the potency of bpV(phen) in vivo confirmed the anti-tumor activity. Further study of the mechanism of action revealed a 40% decrease in Cdk2 kinase activity, an elevated level of Cdk2/p27(kip1), and the appearance of Cdk2/SHP-1 complexes. Therefore, a cytostatic dose of a PTP inhibitor increases the intracellular levels of Cdk2/p27(kip) and Cdk2/SHP-1 complexes, which indicate the presence of additional mechanisms underlying the anti-tumor activity.
    Full-text · Article · May 2008 · Cancer Letters
Show more