The traditional PI3K pathway relies on agonist mediated stimulation of PI3Kα through RTKs and PI3Kγ through GPCRs, which stimulate downstream enzymes such as Akt. This pathway has been found to be important in cardiomyocytes and cardiofibroblasts for regulating cardiac morphology and function. However, evidence has suggested that this traditional pathway does not fully represent the PI3K signaling cascade. We demonstrated that PI3Kγ regulates calcium through kinase independent interactions. PI3KγKO hearts rapidly develop systolic dysfunction and dilated cardiomyopathy in response to pressure overload due to excess matrix metalloproteinase mediated degradation of N-cadherin adhesion complexes. We also show a connection between the PI3K/PTEN and Casein Kinase 2, an enzyme that deactivates PTEN. Finally, our results demonstrate crosstalk between GPCRs and PI3Kα via transactivation of growth factor receptors. Our results provide insight into the regulation and the complexity of the PI3K/PTEN pathway. / Experimental Medicine
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1919 |
| Date | 06 1900 |
| Creators | Guo, Danny |
| Contributors | Gavin Y. Oudit (Medicine), Gary D. Lopaschuk (Pharmacology and Pediatrics), Jason R.B. Dyck (Pediatrics), Joseph Casey (Physiology), Allan Murray (Medicine) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 4752222 bytes, application/pdf |
| Relation | Guo, Danny (2010). http://circres.ahajournals.org/cgi/content/full/107/10/1275 |
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