β-Catenin, Cancer, and G Proteins N

ot Just for Frizzleds Anymore

Ming Yang et al. PNAS. 2005.Maria Domenica Castellone et al. Science. 2005.

G-protein signal pathways and subfamilies.

Ligand

GPCR

G-G

G-GTP G

Ion channels PLC Adenylyl cyclase PI3K GRKs MAP kinase cascade

G

s

i

q

12

i1, i2, i3, oa,t1, t2, gust, z

s, olf

q, 11, 14, 15

12, 13

16 subunits are known.

G

2, 3, 4

5-1, 5-2

6 subunits are known.

G

1, 2, 3, 4, 5, 7, 8, 10, 11, 12, Cone

11 subunits are known.

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 -catenin-Lef-Tcf pathway. Science. 2001.

The relationship between G-protein and Wnt.

CC Malbon et al. BBRC. 2001.

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 -catenin pathway. PNAS. 2005.

Prostaglandin E2 Promotes Colon cancer cell growth through a Gs-Axin--catenin signaling axis. Science. 2005.

Rapid, Wnt-induced changes in GSK3 associations that regulate -catenin stabilization are mediated by G proteins. Curr Biol. 2005.

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

Gi/o

LPA2

Gq G12/13

LPA induces proliferation of colon cancer cells through GSK3phosphorylation, increase of -catenin, expression of target gene.

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

Schematic of G protein–coupled signaling of LPA and Wnts.

CC Malbon. STKE. 2005

Experimental background.

Patients with familial adenomatous polyposis, a disease characterized by the presenceof 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.

PGE2 promotes growth of colon cancer cells through -catenin.

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

Axin coimmunoprecipitation with activated Gs through its RGS domain.

PGE2 stimulation of -catenin activity through a convergentmechanism initiated by Gs and G.

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

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