RACK1 Suppresses Gastric Tumorigenesis by Stabilizing the β-Catenin Destruction Complex
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Gastroenterology
(Impact Factor: 16.72).
01/2012; 142(4):812-823.e15. DOI: 10.1053/j.gastro.2011.12.046
Dysregulation of Wnt signaling has been involved in gastric tumorigenesis by mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1, GNB2L1) is involved in development of different tumor types, but its expression and function have not been investigated in gastric tumors.
We analyzed expression of RACK1 in gastric tumor samples and their matched normal tissues from 116 patients using immunohistochemistry. Effects of knockdown with small interfering RNAs or overexpression of RACK1 in gastric cancer cell lines were evaluated in cell growth and tumor xenograft. RACK1 signaling pathways were investigated in cells and zebrafish embryos using immunoblot, immunoprecipitation, microinjection, and in situ hybridization assays.
Expression of RACK1 was reduced in gastric tumor samples and correlated with depth of tumor infiltration and poor differentiation. Knockdown of RACK1 in gastric cancer cells accelerated their anchorage-independent proliferation in soft agar, whereas overexpression of RACK1 reduced their tumorigenicity in nude mice. RACK1 formed a complex with glycogen synthase kinase Gsk3β and Axin to promote the interaction between Gsk3β and β-catenin and thereby stabilized the β-catenin destruction complex. On stimulation of Wnt3a, RACK1 repressed Wnt signaling by inhibiting recruitment of Axin by Dishevelled 2 (Dvl2). Moreover, there was an inverse correlation between expression of RACK1 and localization of β-catenin to the cytoplasm/nucleus in human gastric tumor samples.
RACK1 negatively regulates Wnt signaling pathway by stabilizing the β-catenin destruction complex and act as a tumor suppressor in gastric cancer cells.
Available from: Steven Francis Grieco
- "Several Axin-binding proteins have been identified that modulate the phosphorylation of β-catenin in the Axin–GSK3 complex (Haraguchi et al., 2008; N.G. Kim et al., 2009; Kashikar et al., 2011; Deng et al., 2012), suggesting that much remains to be learned about how signaling pathways are integrated at this locus. Others have reviewed the details of the β-catenin destruction complex (MacDonald et al., 2009; Valvezan & Klein, 2012; Willert & Nusse, 2012), but there are several important points that are often overlooked by investigators new to the field. "
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ABSTRACT: Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.
Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.016 · 9.72 Impact Factor
Available from: An-Gang Yang
- "Colon cancers almost invariably carry activating mutations in the Wnt/b-catenin pathway, which target the tumor suppressors APC and Axin2 or the oncogene b-catenin. The common denominator of the Wnt pathway is the formation of Tcf/b-catenin complexes and the subsequent uncontrolled target gene's transcription, including c-myc, CCND1, survivin and etc.  . However, although the Wnt/b-catenin signaling is also one of the major causes of hepatocellular and gastric cancer development, unlike colon cancer, APC gene mutations are not common in these types of cancers, and b-catenin mutations are present in fewer than 30% of the Wnt/b-catenin-activated cancers  . "
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Biochemical and Biophysical Research Communications 03/2012; 420(4):787-92. DOI:10.1016/j.bbrc.2012.03.075 · 2.30 Impact Factor
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