Association of Focal Adhesion Kinase with Tuberous Sclerosis Complex 2 in the Regulation of S6 Kinase Activation

Tuberous sclerosis complex 1 (TSC1) and TSC2 tumor sup- pressor proteins have been shown to negatively regulate cell growth through inhibition of the mammalian target of rapamy- cin (mTOR) pathway. Focal adhesion kinase (FAK) is a cytoplas- mic tyrosine kinase that plays a critical role in integrin signaling. Here we identify a novel interaction between FAK and TSC2 and show that TSC2 is phosphorylated by FAK. Furthermore, we show that overexpression of FAK kinase dead mutant inhibits the phosphorylation of ribosomal S6 kinase (S6K) and eukary- otic initiation factor 4E-binding protein-1, two key mTOR (mammalian target of rapamycin) downstream targets, and neg- atively regulates the cell size and that FAK regulation of S6K phosphorylation is through TSC2. Finally, we provide data that FAK plays a positive role in cell adhesion-induced S6K phospho- rylation, whereas TSC2 is required for cell suspension-induced S6K inactivation. Together, these results suggest that FAK might regulate S6K activation and cell size through its interac- tion with and phosphorylation of TSC2 and also provide a pre- viously unappreciated role of TSC2 in the regulation of mTOR signaling by cell adhesion.