Retinoic Acid as a Modulator of the Activity of Protein Kinase C
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- 作者：Marí ; a-José ; Ló ; pez-Andreo ; Alejandro Torrecillas ; Pablo Conesa-Zamora ; Senena Corbalá ; n-Garcí ; a ; and Juan C. Gó ; mez-Ferná ; ndez
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：August 30, 2005
- 年：2005
- 卷：44
- 期：34
- 页码：11353 - 11360
- 全文大小：175K
- 年卷期：v.44,no.34(August 30, 2005)
- ISSN：1520-4995
文摘
All-trans-retinoic acid (atRA) is a derivative of vitamin A and possesses antitumor activity.We demonstrate that atRA is able to modulate the activity of protein kinase C 
(PKC), which is relatedto tumor development. In vitro, it was found that atRA activated PKC in the presence of Ca2+ and inthe absence of phosphatidylserine, although such activity is considerably inhibited in mutations affectingresidues D246 and D248 and also residue N189, all of which are known to be essential for the interactionwith Ca2+ and phosphatidylserine in the C2 domain. It was concluded that atRA substitutes phosphatidylserine although with lower specific activities. However, atRA had a biphasic effect on PKC activityin the presence of activating phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate, yielding activation at low concentrations but inactivation at higher ones. This second inhibitorycharacteristic was not shown with K209 and K211 mutations (residues located in the Lys-rich cluster inthe C2 domain) in PKC. This interesting effect revealed the importance of phospholipid binding at thissite to ensure maximum activity for the wild-type PKC. The C1 domain was not related with the atRAeffect on PKC. It was concluded that whereas atRA may activate PKC through the Ca2+-phosphatidylserine-binding site of the C2 domain, it may also inhibit the activity of this enzyme whendisplacing the phospholipid from the Lys-rich cluster also located in the C2 domain.
(PKC), which is relatedto tumor development. In vitro, it was found that atRA activated PKC in the presence of Ca2+ and inthe absence of phosphatidylserine, although such activity is considerably inhibited in mutations affectingresidues D246 and D248 and also residue N189, all of which are known to be essential for the interactionwith Ca2+ and phosphatidylserine in the C2 domain. It was concluded that atRA substitutes phosphatidylserine although with lower specific activities. However, atRA had a biphasic effect on PKC activityin the presence of activating phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate, yielding activation at low concentrations but inactivation at higher ones. This second inhibitorycharacteristic was not shown with K209 and K211 mutations (residues located in the Lys-rich cluster inthe C2 domain) in PKC. This interesting effect revealed the importance of phospholipid binding at thissite to ensure maximum activity for the wild-type PKC. The C1 domain was not related with the atRAeffect on PKC. It was concluded that whereas atRA may activate PKC through the Ca2+-phosphatidylserine-binding site of the C2 domain, it may also inhibit the activity of this enzyme whendisplacing the phospholipid from the Lys-rich cluster also located in the C2 domain.