Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways

Abstract

Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha). Moreover, TNF-alpha-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.

The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway

“…Furthermore, expression of MEKK1, an upstream activator of JNK/SAPK results in the apoptotic death of ®broblasts , suggesting that under some circumstances, JNK/SAPK signalling alone may be su cient to cause cell death. In other studies, it has been shown that activation of ASK1, a kinase of the JNK/SAPK pathway that functions in response to TNFa is su cient to induce apoptosis and is required for TNFa-induced cell death (Ichijo et al, 1997). From all these studies, it is becoming clear that the regulation of programmed cell death is a very complex phenomenon which varies both with the cell type and the inducer of apoptosis.…”

“…In addition to MEKK1, other kinases have been proposed to function as MAPK kinase kinases including TAK1 (Yamaguchi et al, 1995) and ASK1 (Ichijo et al, 1997). To further dissect the mechanism of activation of JNK/SAPK activation by T/P, we determined the ability of dominant-interfering mutants of TAK1 (TAK1 K63W) and ASK1 (ASK1 KR) to suppress HA-JNK/SAPK activation by T/P.…”

“…Furthermore, JNK/ SAPK activation requires phosphorylation at two residues, Thr-183 and Tyr-185 by the MAPK kinase 4 (MKK4, also called SEK1, MEK4 or JNKK/ SAPKK) Lin et al, 1995;Sanchez et al, 1994), a dual speci®city protein kinase. MKK4 itself is phosphorylated by upstream MAPK kinase kinases such as MEKK1 (Yan et al, 1994), apoptosis signal regulating kinase (ASK1) (Ichijo et al, 1997) or TGF-b-activated kinase 1 (TAK1) (Yamaguchi et al, 1995). Experiments with a series of dominant-inhibitory or constitutively activated mutant proteins have indicated that the Rho family GTPases, Cdc42H and Rac initiate a cascade leading to JNK/SAPK (Coso et al, 1995;Minden et al, 1995), presumably by binding and activating the protein kinase PAK, a kinase that phosphorylates and promotes activation of MEKK1.…”

Genome‐wide examination of myoblast cell cycle withdrawal during differentiation

“…The expression of several pro-apoptotic proteins was down-regulated at D1, including ASK1 (Ichijo et al, 1997), CIDE-B (Inohara et al, 1998), ES18 , Granzyme B (Darmon and Bleackley, 1998), NIP3 (Chen et al, 1997;Yasuda et al, 1998), and the P2X ATP receptor (Brake et al, 1994; Table 2). Paradoxically, expression of the antiapoptotic regulator, IAP-A (Goyal, 2001), decreased more than 50%, whereas expression of NIX (Chen et al, 1999), a pro-apoptotic Bcl-2 family member, increased approximately twofold in differentiating C2C12 cells (Table 2).…”

JNK activation is not required for Fas-mediated apoptosis

“…JNK activation follows recruitment of Daxx, rather than FADD, to the Fas death domain (Yang et al, 1997;Chang et al, 1998) and a dominant negative form of FADD does not block JNK activation by Fas stimulation (Wajant et al, 1998). JNK activation has also been demonstrated during apoptosis in response to irradiation, heat shock, cisplatin, NGF removal, and TNF or ceramide treatment (Chen et al, 1996;Zanke et al, 1996;Xia et al, 1995;Verheij et al, 1996;Cuvillier et al, 1996;Ichijo et al, 1997;Shirakabe et al, 1997).…”