AIP1 mediates TNF-α-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3

Rong Zhang, Xiangrong He, Weimin Liu, Meng Lu, Jer Tsong Hsieh, Wang Min

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Abstract

TNF-α activates ASK1 in part by dissociating 14-3-3 from apoptosis signal-regulating kinase 1 (ASK1). In the present study, we identified a novel Ras GTPase-activating protein (Ras-GAP) as an ASK1-interacting protein (AIP1). AIP1 binds to the C-terminal domain of ASK1 via a lysine-rich cluster within the N-terminal C2 domain. AIP1 exists in a closed form through an intramolecular interaction between the N-terminus and the C-terminus, and TNF-α induces unfolding of AIP1 leading to association of AIP1 with ASK1. Thus, the N-terminus of AIP1 containing the C2 and GAP domains constitutively binds to ASK1 and facilitates the release of 14-3-3 from ASK1. In contrast to 14-3-3, AIP1 binds preferentially to dephosphorylated ASK1. Recruited AIP1 enhances ASK1-induced JNK activation, and the ASK1 binding and the GAP activity of AIP1 are critical for AIP1-enhanced ASK1 activation. Furthermore, TNF-induced ASK1/JNK activation is significantly blunted in cells where AIP1 is knocked down by RNA interference. These data suggest that AIP1 mediates TNF-α-induced ASK1 activation by facilitating dissociation of inhibitor 14-3-3 from ASK1, a novel mechanism by which TNF-α activates ASK1.

Original languageEnglish (US)
Pages (from-to)1933-1943
Number of pages11
JournalJournal of Clinical Investigation
Volume111
Issue number12
DOIs
StatePublished - Jun 2003

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MAP Kinase Kinase Kinase 5
ras GTPase-Activating Proteins

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AIP1 mediates TNF-α-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. / Zhang, Rong; He, Xiangrong; Liu, Weimin; Lu, Meng; Hsieh, Jer Tsong; Min, Wang.

In: Journal of Clinical Investigation, Vol. 111, No. 12, 06.2003, p. 1933-1943.

Research output: Contribution to journalArticle

Zhang, Rong ; He, Xiangrong ; Liu, Weimin ; Lu, Meng ; Hsieh, Jer Tsong ; Min, Wang. / AIP1 mediates TNF-α-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 12. pp. 1933-1943.
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