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2.
BMC Neurosci ; 10: 61, 2009 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-19534784

RESUMO

BACKGROUND: Guanine nucleotide exchange factors (GEFs) and their target Rho GTPases regulate cytoskeletal changes and membrane trafficking. Dynamin, a large force-generating GTPase, plays an essential role in membrane tubulation and fission in cells. Kalirin12, a neuronal RhoGEF, is found in growth cones early in development and in dendritic spines later in development. RESULTS: The IgFn domain of Kalirin12, not present in other Kalirin isoforms, binds dynamin1 and dynamin2. An inactivating mutation in the GTPase domain of dynamin diminishes this interaction and the isolated GTPase domain of dynamin retains the ability to bind Kalirin12. Co-immunoprecipitation demonstrates an interaction of Kalirin12 and dynamin2 in embryonic brain. Purified recombinant Kalirin-IgFn domain inhibits the ability of purified rat brain dynamin to oligomerize in response to the presence of liposomes containing phosphatidylinositol-4,5-bisphosphate. Consistent with this, expression of exogenous Kalirin12 or its IgFn domain in PC12 cells disrupts clathrin-mediated transferrin endocytosis. Similarly, expression of exogenous Kalirin12 disrupts transferrin endocytosis in cortical neurons. Expression of Kalirin7, a shorter isoform which lacks the IgFn domain, was previously shown to inhibit clathrin-mediated endocytosis; the GTPase domain of dynamin does not interact with Kalirin7. CONCLUSION: Kalirin12 may play a role in coordinating Rho GTPase-mediated changes in the actin cytoskeleton with dynamin-mediated changes in membrane trafficking.


Assuntos
Dinaminas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neurônios/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Clatrina/farmacologia , Dinaminas/classificação , Embrião de Mamíferos , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , GTP Fosfo-Hidrolases/metabolismo , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Cones de Crescimento/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Imunoprecipitação/métodos , Lipossomos/metabolismo , Neurônios/citologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Ratos , Transfecção/métodos , Transferrina/metabolismo
3.
Neuroscientist ; 11(2): 148-60, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15746383

RESUMO

A large number of Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase activating proteins (GAPs) are used in the CNS to activate specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, in part through their effects on the actin cytoskeleton. Kalirin is a large neuronal dual Rho GEF that activates Rac1, RhoA, and RhoG via its two Rho GEF domains. This activation, which is spatially and temporally regulated, allows Kalirin to influence neurite initiation, axonal growth, and dendritic morphogenesis. In addition, this alternatively spliced gene generates developmentally regulated transcripts that yield proteins localized to the postsynaptic density (PSD). Kalirin-7, which interacts with PSD-95, is necessary for dendritic spine formation. In addition, Kalirins have the ability to regulate and influence other aspects of neuronal morphogenesis via protein-protein interactions with their other domains, including many spectrins, other protein and lipid interaction domains, and a potential kinase. These interactions have implications not only for neuronal morphogenesis but also for vesicle trafficking, secretion, neuronal maintenance, and neurodegenerative disease.


Assuntos
Sistema Nervoso Central/metabolismo , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Neurônios/metabolismo , Animais , Sistema Nervoso Central/crescimento & desenvolvimento , Citoesqueleto/fisiologia , Proteínas Ativadoras de GTPase/fisiologia , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , Isoformas de Proteínas/fisiologia
4.
Biopreserv Biobank ; 13(5): 311-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26484571

RESUMO

The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community.


Assuntos
Pesquisa Biomédica , Bancos de Tecidos , Obtenção de Tecidos e Órgãos , Pesquisa Biomédica/métodos , Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/normas , Humanos , Obtenção de Tecidos e Órgãos/métodos , Obtenção de Tecidos e Órgãos/organização & administração , Obtenção de Tecidos e Órgãos/normas
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