title: Dyrk1A, a serine/threonine kinase, is involved in ERK and Akt activation in the brain of hyperhomocysteinemic mice.
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.
authors.affiliation: Unit of Functional and Adaptive Biology (BFA), Univ Paris Diderot, Sorbonne Paris Cité, EAC-CNRS 4413, Case 7104, 75205, Paris, cedex 13, France.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Abekhoukh
authors.forename: Chris
authors.initials: C
authors.lastname: Planque
authors.forename: Clémentine
authors.initials: C
authors.lastname: Ripoll
authors.forename: Paulina
authors.initials: P
authors.lastname: Urbaniak
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Delabar
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006247:Harmine / Q000494:pharmacology; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003541:Cystathionine beta-Synthase; D048049:Extracellular Signal-Regulated MAP Kinases; D051380:GRB2 Adaptor Protein; D006247:Harmine; D006710:Homocysteine; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D010768:Phosphoserine; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D000097603:Dyrk Kinases; C118389:Spry2 protein, mouse