Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation.
Focal adhesion kinase (FAK) has an antiapoptotic role in anchorage-dependent cells via an unknown mechanism. To elucidate the role of FAK in the antiapoptosis, we have demonstrated that FAK-overexpressed (HL-60/FAK) cells have marked resistance against various apoptotic stimuli. That is, HL-60/FAK cells were highly resistant to hydrogen peroxide or etoposide-induced apoptosis compared with the vector-transfected cells. In this study, we demonstrated that HL-60/FAK cells were highly resistant to ionizing radiation (IR)-induced apoptosis. IR at 10-40 Gy induced significant DNA fragmentation, activation of caspase-3 and -8, the processing of a proapoptotic BID, and mitochondrial release of cytochrome c in the parental or HL-60/Vect cells, whereas no significant DNA fragmentation or no other concurring events were observed in the HL-60/FAK cells. Of note is that, in the HL-60/FAK cells, phosphatidylinositol 3'-kinase-Akt survival pathway was activated, accompanied with significant induction of inhibitor-of-apoptosis proteins (cIAP-2, XIAP). Finally, constructs of FAK mutants revealed that the central kinase domain (K454), autophosphorylation site (Y397), as well as focal adhesion target regions (Y925), were prerequisite for the FAK function. These results indicated that mitochondria pathway is required for IR-induced apoptosis, and FAK overexpression prevents this pathway, thus rendering antiapoptotic states.
Kasahara
Tadashi
T
Department of Biochemistry, Kyoritsu College of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo, 105-8512, Japan. kasahara-td@kyoritsu-ph.ac.jp
Koguchi
Emiko
E
Funakoshi
Megumi
M
Aizu-Yokota
Eriko
E
Sonoda
Yoshiko
Y
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D053938:DNA Fragmentation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D020169:Caspases; D003574:Cytochrome c Group; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D014443:Tyrosine; C494814:BID protein, human; C030193:immunosuppressive acidic protein; C496050:PTK2 protein, human; C494918:AKT1 protein, human