PTK6 regulates IGF-1-induced anchorage-independent survival.
BACKGROUND
Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival.


RESULTS
We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2(+) breast cancer subtype, but also in high grade ER(+), Luminal B tumors and high expression is associated with adverse outcomes.


CONCLUSIONS
These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action.
Irie
Hanna Y
HY
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
Shrestha
Yashaswi
Y
Selfors
Laura M
LM
Frye
Fabianne
F
Iida
Naoko
N
Wang
Zhigang
Z
Zou
Lihua
L
Yao
Jun
J
Lu
Yiling
Y
Epstein
Charles B
CB
Natesan
Sridaran
S
Richardson
Andrea L
AL
Polyak
Kornelia
K
Mills
Gordon B
GB
Hahn
William C
WC
Brugge
Joan S
JS
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C088375:PTK6 protein, human