Identification and characterization of novel focal adhesion kinase substrates: Programmed cell death 6
Rodrigues Dos Santos, Bruno Filipe
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Focal Adhesion Kinase (FAK) is a major signaling molecule which functions downstream of integrins or in conjunction with mitogenic signaling pathways. FAK is overexpressed and/or activated in many types of human tumors, in which it promotes cell adhesion, survival, migration and invasion. In addition to FAK's ability to regulate signaling through its scaffolding activities, FAK encodes an intrinsic kinase activity. Although some FAK substrates have been identified, a more comprehensive analysis of substrates is lacking. In this study, we use a protein microarray to screen the human proteome for FAK substrates. In particular, we confirm that two of the substrates identified—vitronectin (VTN), and programmed cell death 6 (PDCD6)—are valid in vitro FAK substrates, and appears to show some specificity for FAK among other kinases. Further analysis showed that PDCD6 tyrosine 4 site is the responsible target by the in vitro phosphorylation by FAK. The use of a human cell line permitted to verify that PDCD6 is also a FAK substrate in vivo, being tyrosine at position 4 and 6 involved in this activity, however further analysis is required to demystify the complete mechanism. Our screen therefore represents the first comprehensive study of FAK's kinase function and provides the basis for future in-depth analysis of the role of FAK's kinase activity in the processes of tumorigenesis.