Cdc42-induced Activation of the Mixed-Lineage Kinase SPRKin Vivo

Böck, Barbara C.; Vacratsis, Panayiotis O.; Qamirani, Erion; Gallo, Kathleen A.

doi:10.1074/jbc.275.19.14231

Cited by 74 publications

(47 citation statements)

References 59 publications

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“…MLK3 has also been shown to activate the MAPK p38 kinase pathway via MKK3/6 (Tibbles et al, 1996) and the extracellular signal-related protein kinase (ERK) pathway (Hartkamp et al, 1999). In addition, expression of a dominant negative mutant of MLK3 led to a reduction in the Cdc42-dependent activation of JNK (Teramoto et al, 1996), and MLK3 CRIB domain has been shown to be required for its association with and activation by Cdc42 in human embryonic kidney 293 cells (Bock et al, 2000). Altogether, these studies strongly suggest that MLK3 may be an important element within the mechanism of stress-induced activation of the JNK pathway and of neuronal death.…”

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

confidence: 50%

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

confidence: 50%

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

et al. 2001

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“…Known activators of mixed-lineage kinases include members of the small Rho-family GTPases (34,(38)(39)(40). Among these GTPase molecules are the Rac, Rho, and cdc42 proteins.…”

Section: Dal-1 Activation Of Jnk Is Dependent On Rac1 Activationmentioning

confidence: 99%

Protein 4.1B/Differentially Expressed in Adenocarcinoma of the Lung-1 Functions as a Growth Suppressor in Meningioma Cells by Activating Rac1-Dependent c-Jun-NH2-kinase Signaling

2006

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Meningiomas are the second most common brain tumor in adults, yet comparatively little is presently known about the dysregulated growth control pathways involved in their formation and progression. One of the most frequently observed genetic changes in benign meningioma involves loss of protein 4.1B expression. Previous studies from our laboratory have shown that protein 4.1B growth suppression in meningioma is associated with the activation of the c-Jun-NH 2 -kinase (JNK) pathway and requires localization of a small unique region (U2 domain) of protein 4.1B to the plasma membrane. To define the relationship between protein 4.1B expression and JNK activation, as well as to determine the mechanism of JNK activation by protein 4.1B, we used a combination of genetic and pharmacologic approaches. In this report, we show that protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 (DAL-1) expression in meningioma cells in vitro results in JNK activation, which requires the sequential activation of Src, Rac1, and JNK. In addition, inhibition of Rac1 or JNK activation abrogates protein 4.1B/DAL-1 growth suppression and cyclin A regulation. Last, protein 4.1B/DAL-1 regulation of this critical growth control pathway in meningioma cells requires the presence of the U2 domain. Collectively, these observations provide the first mechanistic insights into the function of protein 4.1B as a growth regulator in meningioma cells.

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“…The small GTPase Cdc42, in its activated state, binds to MLK3 through the centrally located CRIB motif, and increases MLK3 catalytic activity (5)(6)(7). This activation is accompanied by a change in the phosphopeptide map pattern of in vivo labeled MLK3, suggesting that Cdc42 binding induces activating phosphorylation event(s) on MLK3 (7). A leucine zipper that resides NH 2 -terminal to the CRIB motif is necessary for MLK3 homo-oligomerization (8).…”

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confidence: 99%

Autoinhibition of Mixed Lineage Kinase 3 through Its Src Homology 3 Domain

Zhang¹,

Gallo²

2001

Journal of Biological Chemistry

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Mixed lineage kinase 3 (MLK3) is a serine/threonine protein kinase that functions as a mitogen-activated protein kinase kinase kinase to activate the c-Jun NH 2 -terminal kinase pathway. MLK3 has also been implicated as an IB kinase kinase in the activation of NF-B. Amino-terminal to its catalytic domain, MLK3 contains a Src homology 3 (SH3) domain. SH3 domains harbor three highly conserved aromatic amino acids that are important for ligand binding. In this study, we mutated one of these corresponding residues within MLK3 to deliberately disrupt the function of its SH3 domain. This SH3-defective mutant of MLK3 exhibited increased catalytic activity compared with wild type MLK3 suggesting that the SH3 domain negatively regulates MLK3 activity. We report herein that the SH3 domain of MLK3 interacts with full-length MLK3, and we have mapped the site of interaction to a region between the zipper and the Cdc42/Rac interactive binding motif. Interestingly, the SH3-binding region contains not a prolinerich sequence but, rather, a single proline residue. Mutation of this sole proline abrogates SH3 binding and increases MLK3 catalytic activity. Taken together, these data demonstrate that MLK3 is autoinhibited through its SH3 domain. The critical proline residue in the SH3-binding site of MLK3 is conserved in the closely related family members, MLK1 and MLK2, suggesting a common autoinhibitory mechanism among these kinases. Our study has revealed the first example of SH3 domainmediated autoinhibition of a serine/threonine kinase and provides insight into the regulation of the mixed lineage family of protein kinases.Virtually all physiological processes are regulated by reversible protein phosphorylation. Therefore protein kinases and phosphatases should be highly regulated enzymes. Physical interactions with other signaling molecules can modulate protein kinase activity by changing subcellular location, autophosphorylation state, or conformation of a protein kinase. In the absence of intermolecular associations, many kinases are kept in an inhibited state that is maintained by intramolecular interactions.Mixed lineage kinase 3 (MLK3), 1 also called Src homology 3(SH3) domain-containing proline-rich kinase (1), is a serine/ threonine kinase that functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MKKK) to phosphorylate and activate the dual specific kinases, MAPK kinase 4 (MKK4) (2) and MKK7 (3) which, in turn, can phosphorylate and activate c-Jun NH 2 -terminal kinase (JNK). Recent evidence suggests that IB kinase ␣ (IKK␣) and IKK␤ are also substrates of MLK3, and that MLK3 acts as an IKK kinase to activate the NF-B pathway in response to T cell receptor costimulation (4). MLK3 contains several domains that are predicted to mediate protein-protein interactions including an SH3 domain, a leucine zipper, and a Cdc42/Rac interactive binding (CRIB) motif (Fig. 1). The small GTPase Cdc42, in its activated state, binds to MLK3 through the centrally located CRIB motif, and increases MLK3 catalytic activity (5-7...

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Cdc42-induced Activation of the Mixed-Lineage Kinase SPRKin Vivo

Cited by 74 publications

References 59 publications

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

Protein 4.1B/Differentially Expressed in Adenocarcinoma of the Lung-1 Functions as a Growth Suppressor in Meningioma Cells by Activating Rac1-Dependent c-Jun-NH2-kinase Signaling

Autoinhibition of Mixed Lineage Kinase 3 through Its Src Homology 3 Domain

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