RRC ID 28638
Author Tokuda E, Fujita N, Oh-hara T, Sato S, Kurata A, Katayama R, Itoh T, Takenawa T, Miyazono K, Tsuruo T.
Title Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo.
Journal Cancer Res
Abstract The serine/threonine kinase Akt plays a central role in cell survival and proliferation. Its activation is linked to tumorigenesis in several human cancers. Although many Akt substrates have been elucidated, the Akt-binding proteins that regulate Akt function remain unclear. We report herein having identified casein kinase 2-interacting protein-1 (CKIP-1) as an Akt pleckstrin homology (PH) domain-binding protein with Akt inhibitory function. CKIP-1 formed a complex with each Akt isoform (Akt1, Akt2, and Akt3) via its NH2 terminus. Dimerization of CKIP-1 via its leucine zipper (LZ) motif at the COOH terminus was found to be associated with Akt inactivation because deletion of the LZ motif eliminated Akt inhibitory function, although it could still bind to Akt. Expression of the NH2 terminus-deleted CKIP-1 mutant containing the LZ motif, but lacking Akt-binding ability, induced Akt phosphorylation and activation by sequestering the ability of endogenous CKIP-1 to bind to Akt. Stable CKIP-1 expression caused Akt inactivation and cell growth inhibition in vitro. In addition, the growth of stable CKIP-1 transfectants xenografted into nude mice was slower than that of mock transfectants. These results indicate that CKIP-1, a novel Akt PH domain-interacting protein, would be a candidate of tumor suppressor with an Akt inhibitory function.
Volume 67(20)
Pages 9666-76
Published 2007-10-15
DOI 10.1158/0008-5472.CAN-07-1050
PII 67/20/9666
PMID 17942896
MeSH Amino Acid Sequence Animals Binding, Competitive Carrier Proteins / biosynthesis Carrier Proteins / genetics Carrier Proteins / metabolism* Cell Growth Processes / physiology Dimerization Down-Regulation Female Humans Intracellular Signaling Peptides and Proteins Mice Mice, Inbred BALB C Molecular Sequence Data Neoplasms / genetics Neoplasms / metabolism* Neoplasms / pathology* Phosphatidylinositol 3-Kinases / metabolism* Phosphatidylinositols / metabolism Phosphorylation Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism* Signal Transduction Transfection
IF 9.727
Times Cited 44
DNA material pFLAG-CMV-2-WT-human Akt1 (RDB06614) pFLAG-CMV-2-WT-human Akt2 (RDB06615) pFLAG-CMV-2-WT-human Akt3 (RDB06616)