Cloning of a Novel Putative Protein Kinase Having a Leucine Zipper Domain from Human Brain

Reddy, Usha R.; Pleasure, David E

doi:10.1006/bbrc.1994.1972

Cited by 49 publications

(37 citation statements)

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“…In contrast to MAPKs and MAPKKs, the MAPKKKs in the JNK and p38 modules are highly divergent in structure and gene number. To date, eleven di erent MAPKKKs have been identi®ed as upstream activators of JNK pathway (Widmann et al, 1999); MEKK1 (Lange et al, 1993), MEKK2 (Blank et al, 1996), MEKK3 (Blank et al, 1996), MTK1/ MEKK4 (Takekawa et al, 1997;Gerwins et al, 1997), Tpl-2/Cot (Aoki et al, 1991;Salmeron et al, 1996), MUK/DLK/ZPK Holzman et al, 1994;Reddy and Pleasure, 1994), MLK-2/MST (Dorow et al, 1995;Hirai et al, 1997), MLK-3/SPRK/ PTK-1 (Rana et al, 1996;Gallo et al, 1994;Ing et al, 1994), TAK1 (Yamaguchi et al, 1995), ASK1/ MAPKKK5 Ichijo et al, 1997) and ASK2 (Saitoh and Ichijo, unpublished observation)/MAPKKK6 (Wang et al, 1998) have been shown to activate JNKs by overexpression (Figure 1). Of these, MEKK1, MEKK2, MEKK3 and Tpl-2 can also activate the ERK pathway, while only TAK1, ASK1 and MTK1 have been shown to strongly activate p38s as well.…”

Section: Upstream Kinases In the Jnk And P38 Modulesmentioning

confidence: 99%

From receptors to stress-activated MAP kinases

1999

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The cell signaling pathways that culminate in activation of a family of stress-activated MAP kinases are beginning to be de®ned. Determination of cell life and cell death is known to largely depend on the balance of intrinsic life and death signals within cells. Recently, two representative mammalian stress-activated kinases, the JNK and p38 MAP kinases, have been implicated in determination of cell fate by modifying the life, death and di erentiation signals. However, the molecular mechanisms by which extracellular signals are transmitted from membrane receptors to the most upstream kinases in the JNK and p38 signaling modules are not fully understood. This review will provide an overview of current knowledge of molecular links between in¯amma-tory cyokine receptors and stress-activated MAP kinase cascades.

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Section: Upstream Kinases In the Jnk And P38 Modulesmentioning

confidence: 99%

From receptors to stress-activated MAP kinases

1999

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“…The small GTPbinding proteins act via various, multiple downstream mitogenactivated protein (MAP) kinase kinase kinases, depending on the cell type, which bind the active GTP-bound form of the small G-proteins and induce JNK activity and transcriptional activation (Lim et al, 1996;Tapon and Hall, 1997;Van Aelst and D'Souza-Schorey, 1997) (for review, see Johnson, 1999). There are several likely intermediates in the signaling cascades linking Cdc42 to the JNK pathway, including the p21-activated kinases (rat p65PAK/PAK1/PAK ␣, PAK-2/PAK ␥, PAK-3/PAK ␤, and PAK4; Bagrodia et al, 1995;Knaus et al, 1995;Manser et al, 1995;Martin et al, 1995;Brown et al, 1996;Abo et al, 1998), the germinal center kinase (GCK; Pombo et al, 1995), the nickinteracting protein (NIK; Su et al, 1997), MEKK1 and MEKK4 (Fanger et al, 1997;Gerwins et al, 1997), plenty of SH3 (POSH) (Tapon et al, 1998), and the mixed lineage kinase family (MLK1, MLK2, MLK3, DLK, LZK) (Dorow et al, 1993;Holzman et al, 1994;Reddy and Pleasure, 1994;Fan et al, 1996;Hirai et al, 1996;Rana et al, 1996;Teramoto et al, 1996;Tibbles et al, 1996;Hirai et al, 1997;Sakuma et al, 1997;Nagata et al, 1998).…”

Section: Abstract: Apoptosis; Cdc42; Mlk3; Signal Transduction; Sympmentioning

confidence: 99%

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

et al. 2001

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Superior cervical ganglion (SCG) sympathetic neurons die by apoptosis when deprived of nerve growth factor (NGF). It has been shown previously that the induction of apoptosis in these neurons at NGF withdrawal requires both the activity of the small GTP-binding protein Cdc42 and the activation of the c-Jun N-terminal kinase (JNK) pathway. The mixed lineage kinase 3 (MLK3) belongs to a family of mitogen-activated protein (MAP) kinase kinase kinases. MLK3 contains a Cdc42/Rac interactive-binding (CRIB) domain and activates both the JNK and the p38 MAP kinase pathways. In this study the role of MLK3 in the induction of apoptosis in sympathetic neurons has been investigated. Overexpression of an active MLK3 induces activation of the JNK pathway and apoptosis in SCG neurons. In addition, overexpression of kinase dead mutants of MLK3 blocks apoptosis as well as c-Jun phosphorylation induced by NGF deprivation. More importantly, MLK3 activity seems to increase by 5 hr after NGF withdrawal in both differentiated PC12 cells and SCG neurons. We also show that MLK3 lies downstream of Cdc42 in the neuronal death pathway. Regulation of MLK3 in neurons seems to be dependent on MLK3 activity and possibly on an additional cellular component, but not on its binding to Cdc42. These results suggest that MLK3, or a closely related kinase, is a physiological element of NGF withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal death. MLK3 therefore could be an interesting therapeutic target in a number of neurodegenerative diseases involving neuronal apoptosis. Key words: apoptosis; Cdc42; MLK3; signal transduction; sympathetic neurons; Jun kinaseActivation of the c-Jun transcriptional pathway has been shown to be an important regulator of apoptosis of sympathetic neurons induced by nerve growth factor (NGF) withdrawal by both microinjection of antibodies against c-Jun or expression of a c-Jun dominant negative mutant (Estus et al., 1994;Ham et al., 1995). Consistent with these observations, removal of survival factors leads to the activation of c-Jun N-terminal kinase (JNK), either alone or together with p38 mitogen-activated kinase, in a number of neuronal death paradigms, including PC12 cells (Xia et al., 1995), superior cervical ganglion (SCG) neurons (Ham et al., 1995;Eilers et al., 1998), and embryonic motoneurons (Maroney et al., 1998). In addition, phosphorylation of c-Jun and activation of JNK have been observed after neuronal injury in the adult rat brain (Herdegen et al., 1998) (for review, see Mielke and Herdegen, 2000). Taken together, these studies demonstrate that the pathways regulating both the level of c-Jun and its phosphorylation are crucial for the induction of neuronal cell death. Therefore, we were interested in identifying the upstream signaling pathways regulating the activation of the JNK-c-Jun pathway in neurons.Recently, we have shown that, in rat SCG neurons, the Rholike GTPases, Cdc42 and Rac1, are required for NGF withdrawal-induced death and that they induce apoptosis via activation of ...

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“…We have previously reported the cloning of a novel protein, ZPK which has protein serine-threonine kinase activity and is related to the mixed lineage kinase family (Reddy et al, 1994). The mouse homolog of this gene, DLK (Holzman et al, 1994), and the rat homolog, MUK (Hirai et al, 1996), have also been isolated, and have been shown to be associated with the JNK/SAPK pathway Hirai et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation

et al. 1999

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Zipper Protein Kinase (ZPK) is a leucine zipper protein localized to the nucleus which exhibits serine-threonine kinase activity and is associated with the stress dependent signal transduction pathway. ZPK forms heterodimers with leucine zipper containing transcription factors such as the cyclic AMP responsive element binding protein (CREB) and Myc. Furthermore ZPK phosphorylates both Myc and CREB. Overexpression of ZPK in NTera-2 human teratocarcinoma cells results in inhibition of PKA induced transcriptional activation by CREB and prevents retinoic acid induced di erentiation of the cells to neurons. Our results suggest that ZPK sti¯es neural di erentiation of NT-2 cells partly due to its inhibitory e ect on CREB function.

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Cloning of a Novel Putative Protein Kinase Having a Leucine Zipper Domain from Human Brain

Cited by 49 publications

References 0 publications

From receptors to stress-activated MAP kinases

From receptors to stress-activated MAP kinases

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation

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