알림·소식
알림·소식
Hard Lessons in Discovery of Novel PDE Inhibitors: Stay Away from the Catalytic Domain
2010-02-23
- Title: Hard Lessons in Discovery of Novel PDE Inhibitors: Stay Away from the Catalytic Domain
- Speaker: Dr Donald H. Maurice, Queens University, Canada (* CV attached )
- Date & Time: Thursday, February 25, 2010/ 5:00pm~6:00pm
- Venue: Auditorium at Institut Pasteur Korea, Pangyo Techno-valley
- Inquiries: Ms. Jieun Kim(김지은), Scientific Affairs, Institut Pasteur Korea (Tel: 031-8018-8041). *If you’d like to join the seminar, please contact at babunn@ip-korea.org
- Abstract: In the work described in this presentation, we identify and characterize at a molecular level a novel signaling complex that selectively integrates phosphatidylinositol and cAMP signals. Moreover, we show that this integration impacts directly the pro-angiogenic potential of human endothelial cells. Briefly, we identify a novel plasma membrane signaling complex that allows selective compartmentation and regulation of cellular PI3Kγ activity based largely, if not solely, on the identity of its regulatory subunit. We report that the cAMP-hydrolyzing PDE, PDE3B, tethers this novel signaling complex to cholesterol-rich domains of the plasma membrane by virtue of its ability to selectively bind EPAC1 and the p84 regulatory subunit of PI3Kγ through distinct protein-protein interactions. We report that a PDE3B-based cell-permeable peptide antagonizes EPAC1 interactions with PDE3B and that this effect alone was sufficient to promote expression of the PI3Kγ-dependent pro-angiogenic program in cells. This last finding provides proof-of-principle that peptides or peptidomemetics which antagonize PDE3B-EPAC1 interactions may significantly alter cellular functions without the need for further signal amplification. How our cellular models may be combined with available technologies at Institut Pasteur Korea will be discussed: inparticular a rationale for the development of peptidomimetics to regulate PI3Kγ-dependent cellular functions based on their ability to interfere with PDE3B-EPAC1 interactions. Such agents would have wide-ranging therapeutic implications.
- Speaker: Dr Donald H. Maurice, Queens University, Canada (* CV attached )
- Date & Time: Thursday, February 25, 2010/ 5:00pm~6:00pm
- Venue: Auditorium at Institut Pasteur Korea, Pangyo Techno-valley
- Inquiries: Ms. Jieun Kim(김지은), Scientific Affairs, Institut Pasteur Korea (Tel: 031-8018-8041). *If you’d like to join the seminar, please contact at babunn@ip-korea.org
- Abstract: In the work described in this presentation, we identify and characterize at a molecular level a novel signaling complex that selectively integrates phosphatidylinositol and cAMP signals. Moreover, we show that this integration impacts directly the pro-angiogenic potential of human endothelial cells. Briefly, we identify a novel plasma membrane signaling complex that allows selective compartmentation and regulation of cellular PI3Kγ activity based largely, if not solely, on the identity of its regulatory subunit. We report that the cAMP-hydrolyzing PDE, PDE3B, tethers this novel signaling complex to cholesterol-rich domains of the plasma membrane by virtue of its ability to selectively bind EPAC1 and the p84 regulatory subunit of PI3Kγ through distinct protein-protein interactions. We report that a PDE3B-based cell-permeable peptide antagonizes EPAC1 interactions with PDE3B and that this effect alone was sufficient to promote expression of the PI3Kγ-dependent pro-angiogenic program in cells. This last finding provides proof-of-principle that peptides or peptidomemetics which antagonize PDE3B-EPAC1 interactions may significantly alter cellular functions without the need for further signal amplification. How our cellular models may be combined with available technologies at Institut Pasteur Korea will be discussed: inparticular a rationale for the development of peptidomimetics to regulate PI3Kγ-dependent cellular functions based on their ability to interfere with PDE3B-EPAC1 interactions. Such agents would have wide-ranging therapeutic implications.