Rho GEF Lsc is required for normal polarization, migration, and adhesion of formyl-peptide–stimulated neutrophils
| Autor: | Jeffrey B. Young, Daniel J. Lerner, Prashant Kaul, Xun Shen, Sanjeev A. Francis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
RHOA
Neutrophils Immunology Leukocyte homeostasis Bone Marrow Cells Biology Biochemistry chemistry.chemical_compound Mice Cell Movement Proto-Oncogene Proteins Cell Adhesion Animals Guanine Nucleotide Exchange Factors Cell adhesion Cytoskeleton Mice Knockout Phagocytes Cell Polarity Chemotaxis Cell migration Cell Biology Hematology N-Formylmethionine leucyl-phenylalanine Cell biology N-Formylmethionine Leucyl-Phenylalanine chemistry biology.protein sense organs Signal transduction Rho Guanine Nucleotide Exchange Factors |
| Popis: | Neutrophil migration requires continuous reorganization of the cytoskeleton and cellular adhesion apparatus. Chemoattractants initiate intracellular signals that direct this reorganization. The signaling pathways that link chemoattractant receptors to the cytoskeleton and cellular adhesion apparatus are now being defined. Formyl-peptide chemoattractants released from bacteria stimulate G-protein-linked receptors on the surface of neutrophils and regulate the neutrophil cytoskeleton and adhesion apparatus through RhoA-dependent pathways. Lsc is a RhoA guanine nucleotide exchange factor that binds the heterotrimeric G-protein alpha-subunits, Galpha12 and Galpha13. We have disrupted the Lsc gene and demonstrated that formyl-peptide-stimulated Lsc knock-out (KO) neutrophils are unable to generate and sustain a single-dominant pseudopod and migrate with increased speed and reduced directionality. Unexpectedly, we also found that Lsc is required for normal beta2- and beta1-integrin-dependent neutrophil adhesion. Lsc-deficient mice have a peripheral leukocytosis and extramedullary hematopoiesis, demonstrating that Lsc is required for leukocyte homeostasis. Lsc-deficient neutrophils are recruited normally to sites of bacterial peritonitis and chemical dermatitis, indicating that other signaling pathways compensate for the Lsc deficiency in some forms of inflammation. These results demonstrate that Lsc links formyl-peptide receptors to RhoA signaling pathways that regulate polarization, migration, and adhesion in neutrophils and that Lsc is required for leukocyte homeostasis. |
| Databáze: | OpenAIRE |
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