Identification of regulated genes during permanent focal cerebral ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4

Schneider, Armin; Laage, Rico; Ahsen, Oliver von; Fischer, Achim; Rossner, Moritz J.; Scheek, Sigrid; Grünewald, Sylvia; Kuner, Rohini; Weber, Daniela; Krüger, Carola; Klaussner, Bettina; Götz, Bernhard; Hiemisch, Holger; Newrzella, Dieter; Martín-Villalba, Ana; Bach, A.; Schwaninger, Markus

doi:10.1046/j.1471-4159.2003.02228.x

Cited by 48 publications

(45 citation statements)

References 52 publications

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“…It is interesting to note that the two kinases whose interaction we have studied in the context of the cytoskeleton also have a relationship to the cell's stress response. Consistent with this, the activation of MARK and the phosphorylation of its downstream target tau is elevated by cellular stress (Jenkins and Johnson, 2000;Schneider et al, 2004). This might explain the increased phosphorylation of tau at early stages of neurodegeneration in Alzheimer's disease and frontotemporal dementias (Augustinack et al, 2002).…”

Section: Discussionmentioning

confidence: 65%

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the downregulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin-and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks. INTRODUCTIONThe observations reported here originated from a study of the neuronal microtubule-associated protein tau and its abnormal changes in Alzheimer's disease. The function of tau in healthy neurons is to stabilize microtubules and to ensure axonal transport along microtubules. In degenerating neurons, tau is hyperphosphorylated, detaches from microtubules, and aggregates into pathological "paired helical filaments." The detachment from microtubules is achieved most efficiently by phosphorylating the KXGS-motifs in the microtubule-binding domain of tau, and elevated phosphorylation at these sites occurs early in Alzheimer's disease (Augustinack et al., 2002). A search for the responsible kinase lead to the identification of the MARK family of protein kinases (Drewes et al., 1997). They are related to the Par-1 kinases in Caenorhabditis elegans and Drosophila melanogaster, which are involved in the determination of embryonic polarity (reviews, Pellettieri and Seydoux, 2002;Fortini, 2004), and indeed the activity of MARK is important for neuronal polarity as well (Biernat et al., 2002). MARK kinases consist of an N-terminal catalytic domain, followed by UBA, spacer, and tail domains. One requirement for activity is the phosphorylation of a threonine in the activation loop (T208 in MARK2), which keeps the active site accessible to the substrate. In the case of MARKs from mammalian brain this is achieved by the kinase MARKK (Timm et al., 2003). Its activation, like that of MARK, leads to detachment of tau and neuronal degeneration, and similar principles appear to hold for other organisms (Nishimura et al., 2004). On the other hand, as with other multidomain kinases, regulation is likely to take place on several levels (Huse and Kuriyan, 2002). Examples are the binding of a pseudosubstrate peptide int...

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Section: Discussionmentioning

confidence: 65%

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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“…The stress responsiveness of the LKB1/PAR-1 pathway was corroborated by observations in rodents that LKB1 and MARK were upregulated during focal cerebral ischemia and that MARK could be activated by electroconvulsive shock (Schneider et al, 2004;Jeon et al, 2005). It is possible that LKB1 may occupy a nodal position through which various physiological or pathological signals are integrated to regulate PAR-1/MARK and tau.…”

Section: Discussionmentioning

confidence: 71%

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Wang

Imai²,

Lu³

2007

J. Neurosci.

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Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human ␤-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.

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“…Expression of MARK4 was upregulated in glioblastomas, as well as in hepatocellular carcinomas, suggesting a role for MARK4 in tumorigenesis (Beghini et al, 2003;Kato et al, 2001). Furthermore, MARK4 expression was also induced during focal cerebral ischemia, and cell viability of neuronal cells was decreased following the overexpression of MARK4 (Schneider et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

Regulation of the polarity kinases PAR-1/MARK by 14-3-3 interaction and phosphorylation

Göransson

Deák

Wullschleger

et al. 2006

Journal of Cell Science

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Members of the PAR-1/MARK kinase family play critical roles in polarity and cell cycle control and are regulated by 14-3-3 scaffolding proteins, as well as the LKB1 tumour suppressor kinase and atypical protein kinase C (PKC). In this study, we initially investigated the mechanism underlying the interaction of mammalian MARK3 with 14-3-3. We demonstrate that 14-3-3 binding to MARK3 is dependent on phosphorylation, and necessitates the phosphate-binding pocket of 14-3-3. We found that interaction with 14-3-3 was not mediated by the previously characterised MARK3 phosphorylation sites, which led us to identify 15 novel sites of phosphorylation. Single point mutation of these sites, as well as the previously identified LKB1-(T211) and the atypical PKC sites (T564/S619), did not disrupt 14-3-3 binding. However, a mutant in which all 17 phosphorylation sites had been converted to alanine residues (termed 17A-MARK3), was no longer able to bind 14-3-3. Wild-type MARK3 was present in both the cytoplasm and plasma membrane, whereas the 17A-MARK3 mutant was strikingly localised at the plasma membrane. We provide data indicating that the membrane localisation of MARK3 required a highly conserved C-terminal domain, which has been termed kinase-associated domain-1 (KA-1). We also show that dissociation of 14-3-3 from MARK3 did not affect catalytic activity, and that a MARK3 mutant, which could not interact with 14-3-3, was normally active. Finally, we establish that there are significant differences in the subcellular localisation of MARK isoforms, as well as in the impact that atypical PKC overexpression has on 14-3-3 binding and localisation. Collectively, these results indicate that 14-3-3 binding to MARK isoforms is mediated by multiple phosphorylation sites, and serves to anchor MARK isoforms in the cytoplasm.

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Identification of regulated genes during permanent focal cerebral ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4

Cited by 48 publications

References 52 publications

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Regulation of the polarity kinases PAR-1/MARK by 14-3-3 interaction and phosphorylation

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