Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene.

The mutation cluster region in the APC gene defines a region of approximately 660 bp, in which the vast majority of its somatic mutations are found. These mutations disrupt the polypeptide chain, typically eliminating five of the seven repeated sequences of 20 amino acids (aa) each in the central region of the APC protein. To examine the relationship between loss of this structure and loss of function, we constructed APC deletion mutants that progressively truncated the protein across the mutation cluster region.

Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein.

Regulation of cell adhesion and cell signaling by beta-catenin occurs through a mechanism likely involving the targeted degradation of the protein. Deletional analysis was used to generate a beta-catenin refractory to rapid turnover and to examine its effects on complexes containing either cadherin or the adenomatous polyposis coli (APC) protein. The results show that amino-terminal deletion of beta-catenin results in a protein with increased stability that acts in a dominant fashion with respect to wild-type beta-catenin.

Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.

The adenomatous polyposis coli gene (APC) is mutated in most colon cancers. The APC protein binds to the cellular adhesion molecule beta-catenin, which is a mammalian homolog of ARMADILLO, a component of the WINGLESS signaling pathway in Drosophila development. Here it is shown that when beta-catenin is present in excess, APC binds to another component of the WINGLESS pathway, glycogen synthase kinase 3beta (GSK3beta), a mammalian homolog of Drosophila ZESTE WHITE 3.

Functional wild-type and carboxyl-terminal-tagged rat substance P receptors expressed in baculovirus-infected insect Sf9 cells.

The rat substance P (SP) receptor (SPR) was expressed in insect Sf9 cells by infection with recombinant baculovirus. The receptor bound SP with high affinity (KD = 360 pM) and had a rank order of affinity of SP > neurokinin A > neurokinin B. Ligand activation of the receptor resulted in an increase in both inositol lipid hydrolysis and intracellular Ca2+ concentration ([Ca2+]i).

Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein.

The APC tumor-suppressor protein associates with beta-catenin, a cell adhesion protein that is upregulated by the WNT1 oncogene. We examined the effects of exogenous APC expression on the distribution and amount of beta-catenin in a colorectal cancer cell containing only mutant APC. Expression of wild-type APC caused a pronounced reduction in total beta-catenin levels by eliminating an excessive supply of cytoplasmic beta-catenin indigenous to the SW480 colorectal cancer cell line.