Dyrk1A, a Serine/Threonine Kinase, is Involved in ERK and Akt Activation in the Brain of Hyperhomocysteinemic Mice |
| |
Authors: | Sabiha Abekhoukh Chris Planque Clémentine Ripoll Paulina Urbaniak Jean-Louis Paul Jean-Maurice Delabar Nathalie Janel |
| |
Affiliation: | 1. Unit of Functional and Adaptive Biology (BFA), Univ Paris Diderot, Sorbonne Paris Cité, EAC-CNRS 4413, Case 7104, 75205, Paris, cedex 13, France 2. Service de Biochimie, AP-HP, H?pital Européen Georges Pompidou, Paris, France 3. Faculté de Pharmacie, Université Paris-Sud, UMR 1154-INRA, Chatenay-Malabry, France 4. Laboratoire BFA, Université Paris Diderot, Paris 7, Case 7104, 3 rue Marie-Andrée Lagroua Weill Hallé, 75205, Paris, cedex 13, France
|
| |
Abstract: | Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal-regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|