Review
JNK and p38 stresskinases — degenerative effectors of signal-transduction-cascades in the nervous system

https://doi.org/10.1016/S0301-0082(99)00042-8Get rights and content

Abstract

The c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases, SAPKs) and p38 kinases constitute together with extracellular signal-regulated kinases (ERKs) the family of MAP kinases. Whereas the functions of JNKs under physiological conditions are largely unknown, there is raising evidence that JNKs are potent effectors of apoptosis or degeneration of neurons in vitro and in the brain. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated degenerative processes that depend on de novo protein synthesis. At the post-translational level, cytoplasmic degenerative actions of JNKs might comprise inhibition of Bcl-2 and steroid hormone-receptor signaling or hyperphosphorylation of tau; and at transcriptional level, JNKs might trigger the induction of the apoptotic effectors p53 and Fas-Ligand by phosphorylation of c-Jun. The role of p38 is the nervous system is poorly understood, but its activation is also considered as part of the neuronal stress response.

This review informs about the genetic processing, the regulation of activity and the biochemical actions of JNK and p38 isoforms in general. In the second part, we summarize the findings on expression and activation of JNKs and p38 under neurodegenerative condition. A particular focus is also put on the putative function of JNK under physiological conditions and for neuroprotection.

Introduction

In neuronal and non-neuronal cells or tissues, the so-called stress response comprises more or less well defined enzymatic and genetic alterations following stressful stimuli such as deprivation of trophic factors, ionizing radiation, free radicals (H2O2 and peroxynitrite), hypoxia, ischemia, heat shock, production of lipid second messengers such as ceramide or activation of death domain receptors e.g. by extracellular molecules such as TNFα or Fas-ligand (Ip and Davis, 1998, Karin, 1995, Pena et al., 1997). These potentially deleterious stimuli provoke intracellular reactions that either lead to (programmed) cell death or defensive-protective adaptations. The bipartite nature of this response is not completely understood and some of the molecules involved, e.g. the c-Jun N-terminal kinases (JNK, also called stress activated protein kinases, SAPK) and their substrates like the transcription factor c-Jun can be linked to both, neurodegeneration and neuroprotection (Herdegen et al., 1997). The protective and degenerative intracellular signal-transduction-cascades are activated in parallel or branch from a common intermediate and the final outcome, death or survival with putatively functional recovery, is determined by the availability of trophic molecules, transmembranous stimulation or physico-chemical parameters that alter the balance of anti- and pro-degenerative intracellular programs. Branching points exist at various levels along the catalytic stream of the signal-transcription-coupling.

  • A. Already the formation of (soluble) monomers or oligomers can determine apoptotic or physiologic/protective intraneuronal reactions following receptor-ligand-association as shown for the association of NGF=p75 receptor or TNFα=TNFα-receptor-I molecules (Becher et al., 1998, Dechant and Barde, 1997).

  • B. Receptors are the second branching point. The intracellular domain of various receptors can associate with different adaptor molecules resulting in stimulation of specific cascades. For example, the TNF Receptor 1/TRADD complex activates JNK directly through interaction with the noncytotoxic TNF receptor-associated factor protein 2 (TRAF2) whereas activation of NFkB through TNF-R1 requires a protein complex consisting of TRAF2/NIK or RIP. Independently from TRAF2, TNF-R1 induced apoptosis occurs via binding of a complex FADD/FELICE (Natoli et al., 1997, Natoli et al., 1998). The Fas receptor engages two independent pathways to induce cell death: one pathway via DAXX that involves JNK activation is blocked by bcl-2, and a second pathway via FADD/FELICE that is bcl-2 insensitive (Yang et al., 1997c).

  • C. Interestingly, the same signal intermediate can exert different functions in dependence on the activatory upstream enzyme. For example, production of the lipid messenger ceramide by the acid sphingomyelinase leads to cell death including activation of JNK; whereas production of ceramide by the neutral sphingomyelinase is associated with physiological or reparative processes including activation of ERK (Pena et al., 1997).

  • D. Information transfer by kinases is hierarchically organized by cascades of kinases (Fig. 1), and several of these cascades can be activated in parallel such as the cascades of JNKs and ERKs. In this case, kinases can propagate antagonistic programs and such a dualism has been found in starved PC12 cells with JNK and p38 stress kinases as mediators of apoptosis and the facilitating downregulation of ERK (Xia et al., 1995); similar, ionizing radiation or TNFα are strong activators of JNK but not of extracellular signal regulated kinase (ERK), whereas H2O2, another cellular stressor, activates ERK but not JNK at physiological concentrations (Hannun, 1996, Pena et al., 1997). However, the idea of separately operating apoptotic or physiologic/reparative kinase systems is complicated by the possibility of cross-talk at each level of the signal-transduction-coupling. Thus, c-Jun N-terminal kinase kinase (JNKK) activates not only JNK, but also ERK with subsequent stimulation of Elk transcription factors and c-fos induction (Minden and Karin, 1997, Zinck et al., 1995). MEKK1, an upstream kinase of the JNK pathway, links the JNK and NFκB pathways by phosphorylation of IKBα complex with subsequent dissociation of NFκB/IκB (Lee et al., 1997).

  • E. Finally, pre-existing and inducible transcription factors control in the nucleus the realization of different genetic programs in dependence on their phosphorylation and subsequent association with other transcription factors. Thus, following association with CBP or Fos proteins, the c-Jun transcription factor induces CRE- or AP-1-regulated target genes, respectively (Arias et al., 1994), and this operational range attributes c-Jun the role of a nuclear branching point at the downstream level of gene transcription.

There is increasing evidence that neurons respond to stress with activation of signal-transcription-cascades and gene expression that are well analyzed in non-neuronal cells such as immune cells, fibroblasts or tumor cells. These reactions comprise among others the expression and release of interleukins, TNFα or Fas-Ligand (CD95-ligand, APO-1), and their respective receptors (Bruce et al., 1996, Matsuyama et al., 1995); activation of proteases (Nicholson and Thornberry, 1997) and activation of stress kinases JNK or p38 (Herdegen et al., 1998, Mielke et al., 1999a, Xia et al., 1995). Moreover, neurons are responsive to a variety of stressful stimuli that are not (or not yet) considered as ‘typical’ neuronal stressors such as H2O2, ionizing radiation, or ceramide. The insight into these intraneuronal operations is meaningful for two reasons: First, the regulated presence of these molecules enlarge our understanding of their functional repertoire. Second, the above mentioned signal cascades are well defined in non-neuronal cells, and a variety of agonistic or antagonistic molecules has already been tested for analytic or therapeutic purposes (e.g. inhibitors of p38 or JNK) (Table 1) (Badger et al., 1996, Henry et al., 1998, Maroney et al., 1998). These findings raise the possibility to cut down apoptotic pathways or to enhance the protective programs of neurons.

Section snippets

JNK isoforms

The JNK kinases are highly conserved during evolution with an amino acid homology of more than 90% in mammals and more than 70% between mammals and drosophila. JNKs are encoded by three different genes jnk1, jnk2, and jnk3 (Gupta et al., 1996). The jnk1 and jnk2 genes are ubiquitously expressed. In contrast, the jnk3 gene is selectively expressed in the brain, heart and the testis. The transcripts of all three genes are alternatively spliced with two splicing variants of the 3′-end. The

Basal expression and activation under physiological non-degenerating conditions

JNKs are widely distributed in mammalian tissue including the brain. In situ hybridisations have shown that JNKs reveal a rather specific expression pattern (Carletti et al., 1995). jnk1 mRNA is restricted to the endopiriform nucleus and medial habenula in the adult brain; jnk2 and jnk3 mRNAs are widely distributed with a higher intense signal of the jnk2 probe (Carboni et al., 1998). It is not clear, however, whether this distribution pattern might be somewhat false negative since activity of

Isoforms of p38 and control of activation

Besides JNKs and ERKs, the p38 kinases form the third family of MAP kinases. Like JNKs, p38 kinases are highly conserved during evolution. The human p38 is 99% identical to mouse, 89% to Xenopus mkp2 and 52% to yeast HOG1p. The p38 kinases represent a family of four homologous kinases: p38α (Freshney et al., 1994; Han et al., 1997; Lee et al., 1994; Raingeaud et al., 1995; Rouse et al., 1994), p38β (Jiang et al., 1996), p38γ (Cuenda et al., 1997; Lechner et al., 1996) and p38δ (Goedert et al.,

p38 in the mammalian nervous system

p38 kinases are widely distributed in mammalian tissues including brain. Comparable to JNK, p38 kinase is activated in PC12 cells following NGF-triggered differentiation without cell death, and its activation is furthermore enhanced following NGF-withdrawal with subsequent apoptosis (Eilers et al., 1998; Kummer et al., 1997; Xia et al., 1995, Mielke et al., 1999b). In contrast NGF-withdrawal in primary cultures of sympathetic neurons does not lead to activation of p38 (Eilers et al., 1998).

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