Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation.
The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or lo...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-03-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2841635?pdf=render |
| _version_ | 1818668917201043456 |
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| author | Kiran Mahajan Domenico Coppola Sridevi Challa Bin Fang Y Ann Chen Weiwei Zhu Alexis S Lopez John Koomen Robert W Engelman Charlene Rivera Rebecca S Muraoka-Cook Jin Q Cheng Ernst Schönbrunn Said M Sebti H Shelton Earp Nupam P Mahajan |
| author_facet | Kiran Mahajan Domenico Coppola Sridevi Challa Bin Fang Y Ann Chen Weiwei Zhu Alexis S Lopez John Koomen Robert W Engelman Charlene Rivera Rebecca S Muraoka-Cook Jin Q Cheng Ernst Schönbrunn Said M Sebti H Shelton Earp Nupam P Mahajan |
| author_sort | Kiran Mahajan |
| collection | DOAJ |
| description | The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery. |
| first_indexed | 2024-12-17T06:43:56Z |
| format | Article |
| id | doaj.art-7f2b87878a874c4898e87e6d35f2af22 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T06:43:56Z |
| publishDate | 2010-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7f2b87878a874c4898e87e6d35f2af222022-12-21T21:59:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-03-0153e964610.1371/journal.pone.0009646Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation.Kiran MahajanDomenico CoppolaSridevi ChallaBin FangY Ann ChenWeiwei ZhuAlexis S LopezJohn KoomenRobert W EngelmanCharlene RiveraRebecca S Muraoka-CookJin Q ChengErnst SchönbrunnSaid M SebtiH Shelton EarpNupam P MahajanThe AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery.http://europepmc.org/articles/PMC2841635?pdf=render |
| spellingShingle | Kiran Mahajan Domenico Coppola Sridevi Challa Bin Fang Y Ann Chen Weiwei Zhu Alexis S Lopez John Koomen Robert W Engelman Charlene Rivera Rebecca S Muraoka-Cook Jin Q Cheng Ernst Schönbrunn Said M Sebti H Shelton Earp Nupam P Mahajan Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS ONE |
| title | Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. |
| title_full | Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. |
| title_fullStr | Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. |
| title_full_unstemmed | Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. |
| title_short | Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. |
| title_sort | ack1 mediated akt pkb tyrosine 176 phosphorylation regulates its activation |
| url | http://europepmc.org/articles/PMC2841635?pdf=render |
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