Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells.
Akt/PKB is a serine/threonine kinase that promotes tumor cell growth by phosphorylating transcription factors and cell cycle proteins. There is particular interest in finding tumor-specific substrates for Akt to understand how this protein functions in cancer and to provide new avenues for therapeutic targeting. Our laboratory sought to identify novel Akt substrates that are expressed in breast cancer. In this study, we determined that activated Akt is positively correlated with the protein expression of the transcription/translation factor Y-box binding protein-1 (YB-1) in primary breast cancer by screening tumor tissue microarrays. We therefore questioned whether Akt and YB-1 might be functionally linked. Herein, we illustrate that activated Akt binds to and phosphorylates the YB-1 cold shock domain at Ser102. We then addressed the functional significance of disrupting Ser102 by mutating it to Ala102. Following the stable expression of Flag:YB-1 and Flag:YB-1 (Ala102) in MCF-7 cells, we observed that disruption of the Akt phosphorylation site on YB-1 suppressed tumor cell growth in soft agar and in monolayer. This correlated with an inhibition of nuclear translocation by the YB-1(Ala102) mutant. In conclusion, YB-1 is a new Akt substrate and disruption of this specific site inhibits tumor cell growth.
Sutherland
Brent W
BW
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Kucab
Jill
J
Wu
Joyce
J
Lee
Cathy
C
Cheang
Maggie C U
MC
Yorida
Erika
E
Turbin
Dmitry
D
Dedhar
Shoukat
S
Nelson
Colleen
C
Pollak
Michael
M
Leighton Grimes
H
H
Miller
Kathy
K
Badve
Sunil
S
Huntsman
David
D
Blake-Gilks
C
C
Chen
Min
M
Pallen
Catherine J
CJ
Dunn
Sandra E
SE
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D051839:NFI Transcription Factors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D051839:NFI Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt