Cross Talk between Vascular Integrins and Receptor Tyrosine Kinases

Integrin-ECM adhesion regulates many intracellular signaling events, affecting cellular responses such as migration, differentiation, and proliferation. Initiation of integrin-ECM adhesion occurs via two primary mechanisms, generally termed outside-in and inside-out signaling. Inside-out signaling involves the modulation of integrin-ECM affinity via signaling events originating within the cell. Outside-in signaling results from direct integrin-ECM binding, leading to the activation of downstream signaling cascades. Whereas integrin activation can occur via a variety of stimuli, growth factors and their cognate receptor tyrosine kinases (RTKs) are established synergistic signaling partners [8]. Importantly, cross talk between integrin and RTK pathways is necessary for microvascular development and maintenance [9].

Generally, signaling cross talk between vascular integrins and RTKs positively regulates each other's function. For example, the integrin avp3 can physically interact with Flk-1, the VEGF-A receptor tyrosine kinase. avp3-Flk1 association augments VEGF-A-induced Flk-1 phosphorylation and enhances endothelial cell migration on vitronectin, an avb3 ligand. A similar physical link between avb3 and the PDGFR-P has been reported. avb3 interaction with both Flk-1 and PDGFR-P occurs via the avP3 extracellular domain and is independent of growth factor stimulation.

Growth factor regulation of integrin signaling also occurs at the transcriptional level. VEGF treatment of endothelial cells stimulates the transcription of multiple integrin sub-units including av, P3, P5, a1, and a2. In other cases, growth factor stimulation of integrin expression can be quite specific. For example, basic fibroblast growth factor (bFGF)-induced angiogenesis leads to the specific upregula-tion of endothelial avP5 integrin.

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Essentials of Human Physiology

Essentials of Human Physiology

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