In the July 15th issue of G&D, Dr. Suzanne Baker (St. Jude Children’s Research Hospital) and colleagues レポート on their surprising discovery of [b][u]link of PI3K signaling within the mammalian brain. This finding highlights the complexity of this clinically significant cell signaling pathway, and its relevance to the デザイン of small molecule PI3K pathway [b][u]link, to both maximize efficacy and minimize side effects.
The [b][u]link is an intricate signaling cascade that regulates cell survival and growth under normal, as well as pathological conditions. In fact, the [b][u]link is mutated in もっと見る cancer patients than any other. The signaling network is balanced によって the PTEN tumor suppressor [b][u]link.
PTEN (Phosphatase and Tensin Homologue Deleted from Chromosome-10) is recognized as one of the most frequently mutated tumor suppressors in human [b][u]link, and has also been associated with neurological diseases like autism. It functions primarily as a phosphatase (phosphate-group-cleaving enzyme) to antagonize PI3K signaling によって dephosphorylating [b][u]link, the lipid 秒 messenger that signals activation of the PI3K signaling [b][u]link. Loss of PTEN results inside the upregulation of PI3K signaling, through the increased phosphorylation of PI3K effectors such as the molecule, [b][u]link. Thus, the PTEN/PI3K/AKT pathway represents an important target for drug discovery.
To study the role of the [b][u]link downstream effector molecule, PDK1, in mediating the effects of PTEN loss, Dr. Baker and colleagues generated a novel transgenic [b][u]link strain deficient in both PDK1 and PTEN specifically within the brain. The researchers found that while some of the characteristic [b][u]link abnormalities arising from PTEN loss are corrected によって the concomitant deletion of PDK1, others are not: Most notably, PDK1 did not rescue the migration [b][u]link associated with PTEN loss in neurons. PDK1-independent abnormalities in the brains of PTEN-deficient mice suggests that additional, alternate downstream [b][u]link of the PI3K signal exist.
This finding underscores the consideration that, as Dr. Baker explains, “[b][u]link that block downstream effectors in PI3K signaling may not correct all of the defects caused によって loss of PTEN [b][u]link.”
Dr. Baker’s team also observed differential feedback regulation of the PI3K pathway in different CNS cell types. Clinical [b][u]link has shown that some human tumors achieve chemoresistance through the increased phosphorylation of the PI3K downstream component, AKT. Quite surprisingly, Dr. Baker and colleagues found that PDK1 [b][u]link caused a selective, dramatic increase within the phosphorylation of AKT in glial cells, but not neurons, indicating unanticipated cell-type specificity in PI3K feedback [b][u]link inside the brain.
Further research will be needed to determine if PDK1, itself, represents a useful therapeutic target. However, this example of a cell [b][u]link response to PDK1 deletion supports the notion of personalized cancer treatment, in so far as emphasizing the relevance of tumor cell of origin and genotype to help predict which patients will respond positively to specific PI3K inhibitors.
Dr. Baker emphasizes that, likewise, “There may be profound differences inside the effects of inhibitors on different types of normal cells, which could be relevant in terms of side effects induced によって systemic treatment with a pathway inhibitor.”
The [b][u]link is an intricate signaling cascade that regulates cell survival and growth under normal, as well as pathological conditions. In fact, the [b][u]link is mutated in もっと見る cancer patients than any other. The signaling network is balanced によって the PTEN tumor suppressor [b][u]link.
PTEN (Phosphatase and Tensin Homologue Deleted from Chromosome-10) is recognized as one of the most frequently mutated tumor suppressors in human [b][u]link, and has also been associated with neurological diseases like autism. It functions primarily as a phosphatase (phosphate-group-cleaving enzyme) to antagonize PI3K signaling によって dephosphorylating [b][u]link, the lipid 秒 messenger that signals activation of the PI3K signaling [b][u]link. Loss of PTEN results inside the upregulation of PI3K signaling, through the increased phosphorylation of PI3K effectors such as the molecule, [b][u]link. Thus, the PTEN/PI3K/AKT pathway represents an important target for drug discovery.
To study the role of the [b][u]link downstream effector molecule, PDK1, in mediating the effects of PTEN loss, Dr. Baker and colleagues generated a novel transgenic [b][u]link strain deficient in both PDK1 and PTEN specifically within the brain. The researchers found that while some of the characteristic [b][u]link abnormalities arising from PTEN loss are corrected によって the concomitant deletion of PDK1, others are not: Most notably, PDK1 did not rescue the migration [b][u]link associated with PTEN loss in neurons. PDK1-independent abnormalities in the brains of PTEN-deficient mice suggests that additional, alternate downstream [b][u]link of the PI3K signal exist.
This finding underscores the consideration that, as Dr. Baker explains, “[b][u]link that block downstream effectors in PI3K signaling may not correct all of the defects caused によって loss of PTEN [b][u]link.”
Dr. Baker’s team also observed differential feedback regulation of the PI3K pathway in different CNS cell types. Clinical [b][u]link has shown that some human tumors achieve chemoresistance through the increased phosphorylation of the PI3K downstream component, AKT. Quite surprisingly, Dr. Baker and colleagues found that PDK1 [b][u]link caused a selective, dramatic increase within the phosphorylation of AKT in glial cells, but not neurons, indicating unanticipated cell-type specificity in PI3K feedback [b][u]link inside the brain.
Further research will be needed to determine if PDK1, itself, represents a useful therapeutic target. However, this example of a cell [b][u]link response to PDK1 deletion supports the notion of personalized cancer treatment, in so far as emphasizing the relevance of tumor cell of origin and genotype to help predict which patients will respond positively to specific PI3K inhibitors.
Dr. Baker emphasizes that, likewise, “There may be profound differences inside the effects of inhibitors on different types of normal cells, which could be relevant in terms of side effects induced によって systemic treatment with a pathway inhibitor.”
