TY  - JOUR
A1  - Fried, Dorothee
A1  - Böhm, Beate B.
A1  - Krause, Kristin
A1  - Burkhardt, Harald
T1  - ADAM15 protein amplifies focal adhesion kinase phosphorylation under genotoxic stress conditions
T2  - Journal of biological chemistry
N2  - ADAM15, a disintegrin and metalloproteinase, is capable of counteracting genotoxic stress-induced apoptosis by the suppression of caspase-3 activation. A cell line expressing the membrane-bound ADAM15 without its cytoplasmic tail, however, lost this anti-apoptotic property, suggesting a crucial role of the intracellular domain as a scaffold for recruitment of survival signal-transducing kinases. Accordingly, an enhanced phosphorylation of FAK at Tyr-397, Tyr-576, and Tyr-861 was detected upon genotoxic stress by camptothecin in ADAM15-transfected T/C28a4 cells, but not in transfectants expressing an ADAM15 mutant without the cytoplasmic tail. Accordingly, a specific binding of the cytoplasmic ADAM15 domain to the C terminus of FAK could be shown by mammalian two-hybrid, pulldown, and far Western studies. In cells expressing full-length ADAM15, a concomitant activation of Src at Tyr-416 was detected upon camptothecin exposure. Cells transfected with a chimeric construct consisting of the extracellular IL-2 receptor α-chain and the cytoplasmic ADAM15 domain were IL-2-stimulated to prove that the ADAM15 tail can transduce a percepted extracellular signal to enhance FAK and Src phosphorylation. Our studies further demonstrate Src binding to FAK but not a direct Src interaction with ADAM15, suggesting FAK as a critical intracellular adaptor for ADAM15-dependent enhancement of FAK/Src activation. Moreover, the apoptosis induction elicited by specific inhibitors (PP2, FAK 14 inhibitor) of FAK/Src signaling was significantly reduced by ADAM15 expression. The newly uncovered counter-regulatory response to genotoxic stress in a chondrocytic survival pathway is potentially also relevant to apoptosis resistance in neoplastic growth.
KW  - Apoptosis
KW  - Cartilage
KW  - Cartilage Biology
KW  - Chondrocytes
KW  - Focal Adhesion Kinase
KW  - Signaling
KW  - ADAM15
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76645
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-766455
SN  - 0021-9258
VL  - 287.2012
IS  - 25
SP  - 21214
EP  - 21223
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -