CNK1 is a novel Akt interaction partner that promotes cell proliferation through the Akt-FoxO signalling axis.
The scaffold proteins connector enhancer of KSR (CNK) participate in Raf-, Rho- and NF-kappaB-dependent signalling and promote cell differentiation and invasion. In this study, we demonstrate that CNK1 downregulation inhibits, whereas CNK1 overexpression stimulates the proliferation of breast cancer cells and human embryonic kidney cells, respectively. This stimulatory effect depends on a functional phosphatidylinositol-3 kinase (PI3K) pathway because treatment of cells with the PI3K inhibitor, LY294002, abrogates CNK1-induced proliferation. CNK1 interacts with the PI3K effector Akt and knockdown of CNK1 decreases Akt activity in breast cancer cells. CNK1 controls Akt-dependent phosphorylation and transcriptional activity of FoxO, which is a negative regulator of proliferation. Consistent with this, CNK1-induced cell proliferation is blocked by FoxO overexpression. Moreover, CNK1 regulates anchorage-independent proliferation and focus formation of breast cancer cells. CNK1 is predominantly localized at the plasma membrane of breast cancer cells, whereas in non-transformed mammary epithelial cells, CNK1 is cytoplasmatic. Accordingly, CNK1 is found preferentially at the plasma membrane in carcinoma in situ and invasive breast cancer tumours compared with normal breast tissue sections. Analysis of multiple breast cancer samples reveals that CNK1-negative tumours show less Akt activity. Thus, CNK1 promotes oncogenic signalling through Akt in breast cancer cell lines and tumours.
Fritz
R D
RD
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Varga
Z
Z
Radziwill
G
G
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
C500833:CNKSR1 protein, human; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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