Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth.
Tuberous sclerosis complex 1 (TSC1) and TSC2 tumor suppressor proteins have been shown to negatively regulate cell growth through inhibition of the mammalian target of rapamycin (mTOR) pathway. Focal adhesion kinase (FAK) is a cytoplasmic 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 eukaryotic initiation factor 4E-binding protein-1, two key mTOR (mammalian target of rapamycin) downstream targets, and negatively 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 phosphorylation, 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 interaction with and phosphorylation of TSC2 and also provide a previously unappreciated role of TSC2 in the regulation of mTOR signaling by cell adhesion.
Gan
Boyi
B
Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
Yoo
Youngdong
Y
Guan
Jun-Lin
JL
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases