[초청강연] Focal adhesion kinase (FAK) activity: importance in promoting tumor metastasis and identification of a novel signaling ~

창의연구단 공동주최제목이 길어 다시 올립니다. Focal adhesion kinase (FAK) activity: importance inpromoting tumor metastasis and identification of a novel signalingconnection in inflammationSummary: Focal adhesion kinase (FAK) is a ubiquitously-expressed cytoplasmic tyrosine kinase that controls cell motility. FAK is activated by integrins, growth factor receptors, and as a function of tumor progression. We have shown that small molecule inhibition of FAK activity prevents tumor growth and metastasis in orthotopic models of breast cancer. However, oral administration of FAK inhibitors do not discriminate role for FAK in tumor versus stromal cells. To focus on stromal FAK signaling, we created a kinase-dead (KD) knockin point-mutation in FAK by homologous recombination. KD FAK results in an early embryonic lethal phenotype with defects in blood vessel morphogenesis, cell motility-polarity, but not cell proliferation. KD FAK embryos exhibit an enlarged allantois that is lacking vascular cell adhesion molecule-1 (VCAM-1) expression. VCAM-1 expression is induced at sites of inflammation and I will present results showing that FAK activity is an essential regulator of tumor necrosis factor-alpha triggered VCAM-1 expression and that FAK inhibitors can prevent injury-induced vascular inflammation. Secondly, we have created a mouse with conditional hemizygous KD FAK expression within adult mouse endothelial cells (ECs). I will present results identifying beta-catenin as a new FAK substrate and establishing that FAK activity within ECs is essential for VEGF-induced permeability associated with increased tumor metastasis.