FAS-INDUCED PROTEOLYTIC ACTIVATION AND INTRACELLULAR REDISTRIBUTION OF THE STRESS-SIGNALING KINASE MEKK1

Citation
Jc. Deak et al., FAS-INDUCED PROTEOLYTIC ACTIVATION AND INTRACELLULAR REDISTRIBUTION OF THE STRESS-SIGNALING KINASE MEKK1, Proceedings of the National Academy of Sciences of the United Statesof America, 95(10), 1998, pp. 5595-5600
Citations number
29
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
95
Issue
10
Year of publication
1998
Pages
5595 - 5600
Database
ISI
SICI code
0027-8424(1998)95:10<5595:FPAAIR>2.0.ZU;2-Y
Abstract
The stress-activated protein kinase (SAPK, alternatively JNK) is activ ated rapidly by cell stress stimuli such as inflammatory cytokines and oxidative stress, and more slowly by the initiation of the apoptotic cell death response by events such as ligation of the Fas protein. Mit ogen-activated protein kinase/Erk kinase kinase-l (MEKK1) is an activa tor of SAPK, serving as a SAPK-kinase-kinase through intermediate phos phorylation of the SAPK kinase SEK1, By sequencing proteolytic cleavag e products of MEKK1, we found that the proapoptotic protease caspase 3 (CPP32) cleaves MEKK1 after residue D68 both in vivo and in vitro. Cl eavage of MEKK1 after D68 is blocked by viral and chemical protease in hibitors, Cleavage of MEKK1 at D68 changes the intracellular distribut ion of the protein from a Triton insoluble compartment to a Triton-sol uble compartment, reflected in a redistribution from a particulate to a diffuse cytoplasmic staining seen by immunofluorescence. Activation of both SAPK and MEKK1 after Fas ligation is prevented by both viral a nd chemical caspase 3 inhibitors, which in contrast fail to block acti vation of SAPK by rapidly acting cell stresses, Stress factor-induced SAPK signaling is not dependent on caspase 3 function. We propose that two mechanisms of stress signaling through MEKK1 exist. One is rapid, independent of proteases, and occurs in the particulate Triton-insolu ble compartment. The other is more slowly activated and involves liber ation of particulate MEKK1 by proteolytic cleavage and activation by c aspase 3.