JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage¹

Nat Cell Biol, 7: 278-285 (2005)

Speaker: 曾昱豪                           Date:14:10~15:00, May 25, 2005

Commentator: 徐麗君博士                   Place: Room 601

Abstract:

The function of ubiquitously expressed non-receptor tyrosine kinase c-Abl in cytoplasm and nucleus was determined in cell fate². The nucleus c-Abl activates apoptotic signals in response to DNA damage. c-Abl is targeted to nucleus by a kinase-independent mechanism when the cells exposed to ADR, (an DNA-damage agent,) and oxidative stress. Liquid chromatography and tandem-mass spectrometry found out that c-Abl associates with 14-3-3 proteins. 14-3-3 proteins are intracellular acidic proteins participate in many physiological processes including cell apoptosis³. 14-3-3 proteins bind to c-Abl at the RSVpTLP motif and thereby sequester c-Abl into the cytoplasm. Previous study showed that JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. The authors proposed that JNK might regulate the association of c-Abl and 14-3-3 proteins. Consistently, the data displayed that inhibition of JNK attenuate ADR-induced dissociation of c-Abl from 14-3-3, and down-regulation of JNK attenuate nuclear accumulation of c-Abl following DNA damage. All together, JNK phosphorylates 14-3-3 proteins to induce the release of c-Abl from 14-3-3 proteins, and thereby, targeting of c-Abl to the nucleus induces apoptosis. These findings indicate that 14-3-3 proteins are pivotal regulators in apoptosis by cytoplasmic sequestration of c-Abl.

References:

1. Yoshida K. et al. JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol, 7: 278-285 (2005).

2. Kharbanda S. et al. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene, 17: 3309-3318 (1998).

3. Dougherty M. K. and Morrison D. K. Unlocking the code of 14-3-3. J Cell Sci, 117:  1875-1884 (2004).