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.
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.
Tokuda
Emi
E
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Fujita
Naoya
N
Oh-hara
Tomoko
T
Sato
Shigeo
S
Kurata
Atsuo
A
Katayama
Ryohei
R
Itoh
Toshiki
T
Takenawa
Tadaomi
T
Miyazono
Kohei
K
Tsuruo
Takashi
T
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D019281:Dimerization; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C408877:PLEKHO1 protein, human; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt