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β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore

β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore. Ming Yang et al. PNAS . 2005. Maria Domenica Castellone et al . Science . 2005. G-protein signal pathways and subfamilies. Ligand. a s, a olf. a i1, a i2, a i3, a oa,

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β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore

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  1. β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore Ming Yang et al. PNAS. 2005. Maria Domenica Castellone et al. Science. 2005.

  2. G-protein signal pathways and subfamilies. Ligand as, aolf ai1, ai2, ai3, aoa, at1, at2, agust, az GPCR aq, a11, a14, a15 Ga-Gbg a12, a13 Gbg Ga-GTP 16 a subunits are known. • Ion channels • PLCb • Adenylyl cyclase • PI3K • GRKs • MAP kinase cascade Gg g1, g2, g3, g4, g5, g7, g8, g10, g11, g12, gCone 6 b subunits are known. 11 g subunits are known.

  3. The relationship between G-protein and Wnt. • Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signaling. Nature. 1997. • Specific involvement of G proteins in regulation of serum response factor-mediated gene transcription by different receptors.J Biol Chem. 1998. • Activation of a frizzled-2/beta-adrenergic receptor chimera promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via Galphao and Galphat. PNAS. 1999. • Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol. 1999. • G protein signaling from activated rat Frizzled-1 to the b-catenin-Lef-Tcf pathway. Science. 2001.

  4. The relationship between G-protein and Wnt. CC Malbon et al. BBRC. 2001.

  5. The relationship between G-protein and Wnt. • Trimeric G protein-dependent Frizzled signaling in Drosophila. Cell. 2005. • G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the b-catenin pathway. PNAS. 2005. • Prostaglandin E2 Promotes Colon cancer cell growth through a Gs-Axin-b-catenin signaling axis. Science. 2005. • Rapid, Wnt-induced changes in GSK3b associations that regulate b-catenin stabilization are mediated by Ga proteins. Curr Biol. 2005.

  6. Experimental background. Stimulation of LPA could induce proliferation of DLD1, WiDR, and HT29 colon cancer cells. However, the signaling mechanism of LPA-induced cell proliferation in these colon cancer cells was not elucidated. Previous studies have demonstrated that LPA receptors LPA1, LPA2, and LPA3 are overexpressed in several types of tumors and cancer cell lines, including colon cancer cell lines. LPA LPA1 LPA3 LPA2 Ga12/13 Gaq Gai/o

  7. LPA induces proliferation of colon cancer cells through GSK3b phosphorylation, increase of b-catenin, expression of target gene.

  8. cPKC is required for LPA-induced activation of the b-catenin pathway.

  9. Schematic of G protein–coupled signaling of LPA and Wnts. CC Malbon. STKE. 2005

  10. Experimental background. Patients with familial adenomatous polyposis, a disease characterized by the presence of numerous colorectal polyps, harbor germline mutations of one allele of the adenomatous polyposis coli (APC) tumor-suppressor gene and develop colon cancer upon mutational damage or loss of the wild-type allele. Nonsteroidal anti-inflammatory drugs (NSAIDs)—which inhibit two enzymes involved in prostaglandin biosynthesis, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)—reduce the number and size of adenomas in patients with familial adenomatous polyposis and prevent colon cancer development in Apcmin mice. Emerging clinical and experimental evidence now supports a potent antitumorigenic efficacy of NSAIDs in colon cancer and implicates the contribution of COX-2 and one of its metabolites, prostaglandin E2 (PGE2), in colon cancer development.

  11. PGE2 promotes growth of colon cancer cells through b-catenin.

  12. Gs-coupled receptors promote b-catenin activation independently of PKA.

  13. Axin coimmunoprecipitation with activated Gas through its RGS domain.

  14. PGE2 stimulation of b-catenin activity through a convergent mechanism initiated by Gas and Gbg.

  15. Knockdown of axin or GSK-3b, or displacement of GSK-3b from axin, is sufficient to stimulate the b-catenin pathway in DLD1 colon cancer cells.

  16. Schematic representation of b-catenin pathway activation in response to PGE2.

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