Integrin signaling underlies a multitude of biological phenomenon throughout development, physiological homeostasis, chronic disease progression, and cancer malignancy. We are interested in integrin-associated focal adhesion kinase (FAK) signaling in disease models such as vascular inflammation and cancer metastasis. FAK is a protein tyrosine kinase named for its localization to integrin adhesion sites called focal adhesions. FAK is a converging point of cellular signaling via integrins and growth factor receptors. Interestingly, FAK also localizes to the nucleus to regulate gene expression by controlling a number of transcription factors (e.g., p53, GATA4).
Our current research focus is to understand a molecular mechanism how and why FAK shuttles to convey extracellular/adhesion signals to the nucleus. Based on the recent finding that the nuclear-localized FAK limits GATA4 required for vascular cell adhesion molecule-1 (VCAM-1) transcription and VCAM-1 plays a key role in promoting vascular inflammation by facilitating leukocyte recruitment, we are investigating whether nuclear FAK regulates vascular inflammation. We have genetic FAK mouse models to evaluate an inflammatory role of FAK in vascular injury models.
Another area of our research is to explore a mechanism of tumor metastasis via tumor-stroma interaction. Although the typical metastasis of melanoma to the lymph nodes is detrimental to overall survival of melanoma patients, molecular mechanisms of this process remain elusive. We are investigating the role of FAK-mediated VCAM-1 expression on lymphatic vessel endothelium in melanoma metastasis to the lymph nodes, using a genetic mouse model and FAK inhibitors. Successful completion of the project will reveal a highly significant value of FAK inhibitors as a novel drug for prevention of melanoma metastasis.
