24 research outputs found
FlorĂstica de uma ĂĄrea de cerradĂŁo na floresta nacional de Paraopeba - Minas Gerais
Dual FGF-2 and Intergrin α5ÎČ1 Signaling Mediate GRAF-Induced RhoA Inactivation in a Model of Breast Cancer Dormancy
Interactions with the bone marrow stroma regulate dormancy and survival of breast cancer micrometastases. In an in vitro model of dormancy in the bone marrow, we previously demonstrated that estrogen-dependent breast cancer cells are partially re-differentiated by FGF-2, re-express integrin α5ÎČ1 lost with malignant transformation and acquire an activated PI3K/Akt pathway. Ligation of integrin α5ÎČ1 by fibronectin and activation of the PI3K pathway both contribute to survival of these dormant cells. Here, we investigated mechanisms responsible for the dormant phenotype. Experiments demonstrate that integrin α5ÎČ1 controls de novo cytoskeletal rearrangements, cell spreading, focal adhesion kinase rearrangement to the cell perimeter and recruitment of a RhoA GAP known as GRAF. This results in the inactivation of RhoA, an effect which is necessary for the stabilization of cortical actin. Experiments also demonstrate that activation of the PI3K pathway by FGF-2 is independent of integrin α5ÎČ1 and is also required for cortical actin reorganization, GRAF membrane relocalization and RhoA inactivation. These data suggest that GRAF-mediated RhoA inactivation and consequent phenotypic changes of dormancy depend on dual signaling by FGF-2-initiated PI3K activation and through ligation of integrin α5ÎČ1 by fibronectin