The tumour suppressor gene adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours. APC is involved in the proteasome-mediated degradation of beta-catenin, through its interaction with beta-catenin, GSK-3 beta and Axin. APC also interacts with the microtubule cytoskeleton and has been localized to clusters near the distal ends of microtubules at the edges of migrating epithelial cells. Moreover, in Xenopus laevis epithelial cells, APC has been shown to move along microtubules and accumulate at their growing plus ends. However, the mechanism of APC accumulation and the nature of these APC clusters remain unknown. We show here that APC interacts with the kinesin superfamily (KIF) 3A-KIF3B proteins, microtubule plus-end-directed motor proteins, through an association with the kinesin superfamily-associated protein 3 (KAP3). The interaction of APC with KAP3 was required for its accumulation in clusters, and mutant APCs derived from cancer cells were unable to accumulate efficiently in clusters. These results suggest that APC and beta-catenin are transported along microtubules by KAP3-KIF3A-KIF3B, accumulate in the tips of membrane protrusions, and may thus regulate cell migration.
LATS2 is a human homolog of Drosophila tumor suppressor lats/warts, and encodes a mitotic kinase whose physiological roles remain to be elucidated. We performed yeast two-hybrid screening and identified a LIM protein Ajuba, as a binding partner of LATS2. LATS2 was localized to the centrosomes throughout the cell cycle and was associated with Ajuba during mitosis, contributing to latter's mitotic phosphorylation. Depletion of LATS2 or Ajuba impaired centrosomal accumulation of c-tubulin and spindle formation at the onset of mitosis, suggesting that the LATS2-Ajuba complex regulates organization of the spindle apparatus through recruitment of c-tubulin to the centrosome.
We have identified and characterized a novel member of the G protein-coupled receptor (GPCR) family, termed DREG. DREG belongs to the LNB-TM7 subfamily and possesses a long aminoterminus that contains a CUB domain, a PTX domain, a hormone binding domain and a GPCR proteolytic site (GPS) domain. RT-PCR experiments and whole mount in situ hybridization in mice showed that DREG is expressed at high levels in the heart and somite during embryogenesis and in the adult lung. When DREG was transiently expressed in mammalian cultured cells, a 35-kD fragment was generated by endogenous proteolytic processing at the conserved GPS domain. This short fragment was found associated with the cell membrane, typical of GPCRs. DREG was further cleaved in the middle of the extracellular domain, generating a soluble 70-kD fragment containing the CUB and PTX domains. This processing was inhibited by an inhibitor of the endoprotease furin but not of matrix metalloproteinases. These results raise the possibility that DREG plays a role in development, not only as a receptor or an adhesion molecule but also as a secreted ligand.
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