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

Wang, Jiwu; Imai, Yuzuru; Lu, Bingwei

doi:10.1523/jneurosci.5094-06.2007

Cited by 72 publications

(88 citation statements)

References 53 publications

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“…Future investigations should determine whether metabolic stress, environmental insults, or other pathological situations known to activate AMPK, could impact brain development through its ability to modulate axon formation, axon growth, and maybe other aspects of neuronal differentiation. Our results have important implications in the context of neurodegeneration especially in light of recent results suggesting that in Drosophila, neurodegeneration induced by Par1 (MARK)-mediated Tau-hyperphosphorylation can be significantly suppressed by reducing LKB1 expression (37,38). Future experiments should further explore the relationship between metabolic stress, AMPK activation, and axon formation, growth, or maintenance in the context of neurodegeneration.…”

Section: Discussionmentioning

confidence: 64%

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress

Williams¹,

Courchet

Viollet

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

109

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Mammalian brain connectivity requires the coordinated production and migration of billions of neurons and the formation of axons and dendrites. The LKB1/Par4 kinase is required for axon formation during cortical development in vivo partially through its ability to activate SAD-A/B kinases. LKB1 is a master kinase phosphorylating and activating at least 11 other serine/threonine kinases including the metabolic sensor AMP-activated protein kinase (AMPK), which defines this branch of the kinome. A recent study using a gene-trap allele of the β1 regulatory subunit of AMPK suggested that AMPK catalytic activity is required for proper brain development including neurogenesis and neuronal survival. We used a genetic lossof-function approach producing AMPKα1/α2-null cortical neurons to demonstrate that AMPK catalytic activity is not required for cortical neurogenesis, neuronal migration, polarization, or survival. However, we found that application of metformin or AICAR, potent AMPK activators, inhibit axogenesis and axon growth in an AMPK-dependent manner. We show that inhibition of axon growth mediated by AMPK overactivation requires TSC1/2-mediated inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. Our results demonstrate that AMPK catalytic activity is not required for early neural development in vivo but its overactivation during metabolic stress impairs neuronal polarization in a mTOR-dependent manner.A MP-activated kinase (AMPK) is a heterotrimeric serine/ threonine protein kinase composed of one catalytic subunit (encoded by α1 or α2 genes in mammals) and two regulatory subunits β and γ (encoded by β1 or β2 genes and γ1, γ2, or γ3 genes, respectively) (1-3). AMPK is an important metabolic sensor, activated by various forms of metabolic stress including low ATP: AMP ratios. AMPK has been implicated in a range of cell biological functions including cell polarity, autophagy, apoptosis, and cell migration (2-9). A recent study (10) suggested that the regulatory subunit, AMPKβ1, is critical for normal neurogenesis, neuronal differentiation, and neuronal survival during cortical development. However, to date there is no published evidence reporting the consequence of a genetic loss of function for the catalytic activity of mammalian AMPK in the mammalian nervous system. To assess the role of AMPKα during cortical development, we used transgenic mice that were ubiquitously inactivated for the AMPKα1 gene (AMPKα1 −/− ) (11) and conditionally inactivated for AMPKα2 (AMPKα2 F/F ) (12, 13). AMPKα2 was selectively deleted using the Emx1 Cre mouse line, which induces recombination only in dorsal telencephalic progenitors giving rise to all pyramidal projection neurons in the cortex, but not in ventral telencephalon-derived cortical GABAergic interneurons, which constitutes ∼25% of all cortical neurons (14). Surprisingly, we found no obvious defect of neurogenesis, neuronal migration, axon formation, or neuronal survival in AMPKα1/2-null cortex compared with control mice. On the basis of the profound di...

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Section: Discussionmentioning

confidence: 64%

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress

Williams¹,

Courchet

Viollet

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Analogously, NUAK1, also known as AMPKrelated protein kinase 5, was the downstream molecule of Akt, which participated in the classical signaling pathway with extensive consequences [63]. Numerous studies have confirmed that Akt-ARK5 was closely related to cancer development and metastasis through blocking cell apoptosis by the inhibition of caspase 8 activation [64,65].…”

Section: +mentioning

confidence: 99%

WITHDRAWN: Genome-wide association analysis of inguinal/scrotal hernia in pigs using specific length amplified fragment (SLAF) sequencing

Zou¹,

Zuo²,

Zhu³

et al. 2017

Oncotarget

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Inguinal and scrotal hernias are the most frequent congenital disorders in pigs, and they may cause severe economic loss in the pig breeding industry. Genetic factors play a significant role in the susceptibility to hernias, but the genetic mechanisms of inguinal/scrotal hernia are poorly understood. In this study, we performed a genome-wide association study (GWAS) with specific-locus amplified fragment sequencing (SLAF-seq) on 120 (59 cases and 61 controls) full and half sib pigs to identify genetic loci underlying variations in inguinal/scrotal hernias. A total of 218,460 high-quality SNPs were generated for further statistical analysis with casecontrols and the farmCPU model. Based on these two methods, a total of 59 SNPs were significantly (P < 0.01) associated with inguinal/scrotal hernia. Finally, 14 novel candidate genes implicated in the defect were identified, and 5 genes (CPNE5, DEGS1, PLCG2, PRKCE and NUAK1) were related to cell apoptosis, which is one of the pivotal pathogenesis factors of inguinal/scrotal hernia. In addition, 4 of them were shown strong associations with the hernia were confirmed in 270 samples (P < 0.05). This finding provides new evidence that genes related to cell apoptosis may be associated with inguinal/scrotal hernias.

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“…These data are consistent with a functional role for the UBA domains in stabilizing an open conformation of the N-and C-terminal lobes of the kinase domain through interactions with the N-lobe (as observed in the kinase:UBA domain crystal structures), which in turn exposes the kinase domain activation segment for phosphorylation by LKB1/Par4. LKB1/Par4-mediated phosphorylation of the Par1/MARK activation segment threonine increases kinase activity Ͼ50-fold in vitro (36) and activates Drosophila Par1 in vivo (37).…”

Section: Conformational Instability Modifies the Ligand-binding Propementioning

confidence: 99%

Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain

Murphy

Korzhnev

Ceccarelli

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The Par-1/MARK protein kinases play a pivotal role in establishing cellular polarity. This family of kinases contains a unique domain architecture, in which a ubiquitin-associated (UBA) domain is located C-terminal to the kinase domain. We have used a combination of x-ray crystallography and NMR dynamics experiments to understand the interaction of the human (h) MARK3 UBA domain with the adjacent kinase domain as compared with ubiquitin. The x-ray crystal structure of the linked hMARK3 kinase and UBA domains establishes that the UBA domain forms a stable intramolecular interaction with the N-terminal lobe of the kinase domain. However, solution-state NMR studies of the isolated UBA domain indicate that it is highly dynamic, undergoing conformational transitions that can be explained by a folding-unfolding equilibrium. NMR titration experiments indicated that the hMARK3 UBA domain has a detectable but extremely weak affinity for monoubiquitin, which suggests that conformational instability of the isolated hMARK3 UBA domain attenuates binding to ubiquitin despite the presence of residues typically involved in ubiquitin recognition. Our data identify a molecular mechanism through which the hMARK3 UBA domain has evolved to bind the kinase domain, in a fashion that stabilizes an open conformation of the Nand C-terminal lobes, at the expense of its capacity to engage ubiquitin. These results may be relevant more generally to the 30% of UBA domains that lack significant ubiquitin-binding activity, and they suggest a unique mechanism by which interaction domains may evolve new binding properties.catalytic domain ͉ dynamics ͉ Par-1 ͉ relaxation ͉ ubiquitin-associated

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

Cited by 72 publications

References 53 publications

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress

WITHDRAWN: Genome-wide association analysis of inguinal/scrotal hernia in pigs using specific length amplified fragment (SLAF) sequencing

Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain

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