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...

Descripción completa

Detalles Bibliográficos
Autores principales: Irie, Hanna Y., Shrestha, Yashaswi, Selfors, Laura M., Frye, Fabianne, Iida, Naoko, Wang, Zhigang, Zou, Lihua, Yao, Jun, Lu, Yiling, Epstein, Charles B., Natesan, Sridaran, Richardson, Andrea L., Polyak, Kornelia, Mills, Gordon B., Hahn, William C., Brugge, Joan S.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909213/
https://www.ncbi.nlm.nih.gov/pubmed/20668531
http://dx.doi.org/10.1371/journal.pone.0011729
_version_ 1782184288493502464
author Irie, Hanna Y.
Shrestha, Yashaswi
Selfors, Laura M.
Frye, Fabianne
Iida, Naoko
Wang, Zhigang
Zou, Lihua
Yao, Jun
Lu, Yiling
Epstein, Charles B.
Natesan, Sridaran
Richardson, Andrea L.
Polyak, Kornelia
Mills, Gordon B.
Hahn, William C.
Brugge, Joan S.
author_facet Irie, Hanna Y.
Shrestha, Yashaswi
Selfors, Laura M.
Frye, Fabianne
Iida, Naoko
Wang, Zhigang
Zou, Lihua
Yao, Jun
Lu, Yiling
Epstein, Charles B.
Natesan, Sridaran
Richardson, Andrea L.
Polyak, Kornelia
Mills, Gordon B.
Hahn, William C.
Brugge, Joan S.
author_sort Irie, Hanna Y.
collection PubMed
description 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. METHODS AND 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.
format Text
id pubmed-2909213
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-29092132010-07-28 PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival Irie, Hanna Y. Shrestha, Yashaswi Selfors, Laura M. Frye, Fabianne Iida, Naoko Wang, Zhigang Zou, Lihua Yao, Jun Lu, Yiling Epstein, Charles B. Natesan, Sridaran Richardson, Andrea L. Polyak, Kornelia Mills, Gordon B. Hahn, William C. Brugge, Joan S. PLoS One Research Article 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. METHODS AND 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. Public Library of Science 2010-07-23 /pmc/articles/PMC2909213/ /pubmed/20668531 http://dx.doi.org/10.1371/journal.pone.0011729 Text en Irie et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Irie, Hanna Y.
Shrestha, Yashaswi
Selfors, Laura M.
Frye, Fabianne
Iida, Naoko
Wang, Zhigang
Zou, Lihua
Yao, Jun
Lu, Yiling
Epstein, Charles B.
Natesan, Sridaran
Richardson, Andrea L.
Polyak, Kornelia
Mills, Gordon B.
Hahn, William C.
Brugge, Joan S.
PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title_full PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title_fullStr PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title_full_unstemmed PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title_short PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival
title_sort ptk6 regulates igf-1-induced anchorage-independent survival
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909213/
https://www.ncbi.nlm.nih.gov/pubmed/20668531
http://dx.doi.org/10.1371/journal.pone.0011729
work_keys_str_mv AT iriehannay ptk6regulatesigf1inducedanchorageindependentsurvival
AT shresthayashaswi ptk6regulatesigf1inducedanchorageindependentsurvival
AT selforslauram ptk6regulatesigf1inducedanchorageindependentsurvival
AT fryefabianne ptk6regulatesigf1inducedanchorageindependentsurvival
AT iidanaoko ptk6regulatesigf1inducedanchorageindependentsurvival
AT wangzhigang ptk6regulatesigf1inducedanchorageindependentsurvival
AT zoulihua ptk6regulatesigf1inducedanchorageindependentsurvival
AT yaojun ptk6regulatesigf1inducedanchorageindependentsurvival
AT luyiling ptk6regulatesigf1inducedanchorageindependentsurvival
AT epsteincharlesb ptk6regulatesigf1inducedanchorageindependentsurvival
AT natesansridaran ptk6regulatesigf1inducedanchorageindependentsurvival
AT richardsonandreal ptk6regulatesigf1inducedanchorageindependentsurvival
AT polyakkornelia ptk6regulatesigf1inducedanchorageindependentsurvival
AT millsgordonb ptk6regulatesigf1inducedanchorageindependentsurvival
AT hahnwilliamc ptk6regulatesigf1inducedanchorageindependentsurvival
AT bruggejoans ptk6regulatesigf1inducedanchorageindependentsurvival