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1.
Nat Neurosci ; 16(4): 407-15, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23416450

RESUMO

The development of neuronal networks in the neocortex depends on control mechanisms for mitosis and migration that allow newborn neurons to find their accurate position. Multiple mitogens, neurotrophic factors, guidance molecules and their corresponding receptors are involved in this process, but the mechanisms by which these signals are integrated are only poorly understood. We found that TrkB and TrkC, the receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are activated by epidermal growth factor receptor (EGFR) signaling rather than by BDNF or NT-3 in embryonic mouse cortical precursor cells. This transactivation event regulated migration of early neuronal cells to their final position in the developing cortex. Transactivation by EGF led to membrane translocation of TrkB, promoting its signaling responsiveness. Our results provide genetic evidence that TrkB and TrkC activation in early cortical neurons do not depend on BDNF and NT-3, but instead on transactivation by EGFR signaling.


Assuntos
Movimento Celular/fisiologia , Fator de Crescimento Epidérmico/fisiologia , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Ativação Transcricional/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Gravidez , Receptor trkB/genética , Receptor trkC/genética , Transdução de Sinais/fisiologia
2.
J Biol Chem ; 281(25): 17321-17336, 2006 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-16603546

RESUMO

BAD is a Bcl-2 homology domain 3 (BH3)-only proapoptotic member of the Bcl-2 protein family that is regulated by phosphorylation in response to survival factors. Binding of BAD to mitochondria is thought to be exclusively mediated by its BH3 domain. We show here that BAD binds to lipids with high affinities, predominantly to negatively charged phospholipids, such as phosphatidylserine, phosphatidic acid, and cardiolipin, as well as to cholesterol-rich liposomes. Two lipid binding domains (LBD1 and LBD2) with different binding preferences were identified, both located in the C-terminal part of the BAD protein. BAD facilitates membrane translocation of Bcl-XL in a process that requires LBD2. Integrity of LBD1 and LBD2 is also required for proapoptotic activity in vivo. Phosphorylation of BAD does not affect membrane binding but renders BAD susceptible to membrane extraction by 14-3-3 proteins. BAD can be removed efficiently by 14-3-3zeta, -eta, -tau and lesxs efficiently by other 14-3-3 isoforms. The assembled BAD.14-3-3 complex exhibited high affinity for cholesterol-rich liposomes but low affinity for mitochondrial membranes. We conclude that BAD is a membrane-associated protein that has the hallmarks of a receptor rather than a ligand. Lipid binding is essential for the proapoptotic function of BAD in vivo. The data support a model in which BAD shuttles in a phosphorylation-dependent manner between mitochondria and other membranes and where 14-3-3 is a key regulator of this relocation. The dynamic interaction of BAD with membranes is tied to activation and membrane translocation of Bcl-XL.


Assuntos
Proteínas 14-3-3/química , Proteína de Morte Celular Associada a bcl/fisiologia , Animais , Apoptose , Membrana Celular/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Células NIH 3T3 , Células PC12 , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/química
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