Molecular interplays of membrane receptors in response to mechanical and chemical stimuli: Roles of integrins, Flk-1 and VE-cadherin.

摘要

Vascular endothelium provides a barrier separating the vessel wall from the flowing blood. Hence, endothelial cells (ECs) are continuously exposed to a variety of external cues, including mechanical (e.g., shear stress) and chemical (e.g., growth factors) stimuli. Membrane receptors in ECs, being located at the interface between the cytoplasm and the external environment, function as transducers conveying messages from outside into the cells. The aim of this study is to investigate the roles of membrane receptors and their interactions in regulating downstream signaling pathways in response to mechanical and chemical stimuli. The results in the present study indicate that shear stress activates integrins, which subsequently trans-activate VEGF receptor 2 (Flk-1). The chemical ligand VEGF and mechanical shear stress both act on Flk-1 to cause the recruitment of the adapter protein Cb1 to Flk-1, which in turn activates Akt and regulates downstream IKK/NFκB signaling pathway. VEGF induces the association of Flk-1 with the adapter protein Nckβ in regulating the JNK signaling pathway; in contrast, shear stress activates JNK independent of Flk-1 and Nckβ. Further studies revealed that the activation of integrins by their engagement with extracellular matrix (ECM) proteins leads to the down-regulation of VE-cadherin-mediated cell-cell adhesion via a Src-dependent, but Ras-independent, pathway. Shear stress, which is known to induce integrin-activation, may modulate VE-cadherin and its related cell-cell adhesion via integrins. In summary, integrins may function as a transducing sensor in response to shear stress and trans-regulate other membrane receptors, including Flk-1 and VE-cadherin. The signaling events induced by the ligand VEGF and mechanical shear stress converge at the membrane receptor Flk-1 in regulating IKK/NFκB, but there is a subsequent divergence in the selective recruitment of adapter proteins to Flk-1 and an eventual convergence in the regulation of JNK. Therefore, my study indicates that different types of membrane receptors do not function in isolation. Instead, they form a molecular network which is well organized for responding appropriately to different stimuli and regulating differentially the downstream signaling pathways.