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J Immunol ; 173(8): 4985-93, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15470041

RESUMO

Lymphocytes circulate in the blood and upon chemokine activation rapidly bind, where needed, to microvasculature to mediate immune surveillance. Resorption of microvilli is an early morphological alteration induced by chemokines that facilitates lymphocyte emigration. However, the antecedent molecular mechanisms remain largely undefined. We demonstrate that Rac1 plays a fundamental role in chemokine-induced microvillar breakdown in human T lymphocytes. The supporting evidence includes: first, chemokine induces Rac1 activation within 5 s via a signaling pathway that involves Galphai. Second, constitutively active Rac1 mediates microvilli disintegration. Third, blocking Rac1 function by cell permeant C-terminal "Trojan" peptides corresponding to Rac1 (but not Rac2, Rho, or Cdc42) blocks microvillar loss induced by the chemokine stromal cell-derived factor 1alpha (SDF-1alpha). Furthermore, we demonstrate that the molecular mechanism of Rac1 action involves dephosphorylation-induced inactivation of the ezrin/radixin/moesin (ERM) family of actin regulators; such inactivation is known to detach the membrane from the underlying actin cytoskeleton, thereby facilitating disassembly of actin-based peripheral processes. Specifically, ERM dephosphorylation is induced by constitutively active Rac1 and stromal cell-derived factor 1alpha-induced ERM dephosphorylation is blocked by either the dominant negative Rac1 construct or by Rac1 C-terminal peptides. Importantly, the basic residues at the C terminus of Rac1 are critical to Rac1's participation in ERM dephosphorylation and in microvillar retraction. Together, these data elucidate new roles for Rac1 in early signal transduction and cytoskeletal rearrangement of T lymphocytes responding to chemokine.


Assuntos
Quimiocinas/farmacologia , Microvilosidades/ultraestrutura , Neuropeptídeos/fisiologia , Linfócitos T/ultraestrutura , Proteínas rac de Ligação ao GTP , Proteínas rac1 de Ligação ao GTP/fisiologia , Actinas/metabolismo , Proteínas Sanguíneas/metabolismo , Quimiocina CXCL12 , Quimiocinas CXC/farmacologia , Proteínas do Citoesqueleto/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neuropeptídeos/química , Fosfoproteínas/metabolismo , Fosforilação , Linfócitos T/efeitos dos fármacos , Proteína cdc42 de Ligação ao GTP/fisiologia , Proteínas rac1 de Ligação ao GTP/química
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