STRAD pseudokinases regulate axogenesis and LKB1 stability

Veleva-Rotse, Biliana O.; Smart, James L.; Baas, Annette F.; Edmonds, Benjamin; Zhao, Zi Ming; Brown, Allyson; Klug, Lillian R.; Hansen, Kelly; Reilly, Gabrielle; Gardner, Alexandria P.; Subbiah, Krishnaveni; Gaucher, Eric A.; Clevers, Hans; Barnes, Anthony P.

doi:10.1186/1749-8104-9-5

Cited by 20 publications

(17 citation statements)

References 49 publications

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“…Furthermore, the phosphorylation level of SAD kinases, downstream effectors of LKB1, is dramatically decreased in the LKB1 -deficient cerebral cortex, and the downregulation of SAD-A and SAD-B rescues the phenotype of multiple axon formation that is induced by LKB1 overexpression in vitro (Barnes et al, 2007 ), suggesting that SAD kinases mediate LKB1 to execute axon specification. In support of these studies on STRAD and SAD, either STRADα/β or SAD-A/-B double-knockout (KO) mice lack axons in the cortex (Kishi et al, 2005 ; Veleva-Rotse et al, 2014 ). SAD kinases regulate the phosphorylation of microtubule-associated proteins, such as tau, leading to alteration in microtubule organization that is critical for axon specification (Mandell and Banker, 1996 ; Kishi et al, 2005 ).…”

Section: Functions Of Lkb1 In Neural Developmentmentioning

confidence: 97%

Versatile Roles of LKB1 Kinase Signaling in Neural Development and Homeostasis

Kuwako

2018

Front. Mol. Neurosci.

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Kinase signaling pathways orchestrate a majority of cellular structures and functions across species. Liver kinase B1 (LKB1, also known as STK11 or Par-4) is a ubiquitously expressed master serine/threonine kinase that plays crucial roles in numerous cellular events, such as polarity control, proliferation, differentiation and energy homeostasis, in many types of cells by activating downstream kinases of the AMP-activated protein kinase (AMPK) subfamily members. In contrast to the accumulating evidence for LKB1 functions in nonneuronal tissues, its functions in the nervous system have been relatively less understood until recently. In the brain, LKB1 initially emerged as a principal regulator of axon/dendrite polarity in forebrain neurons. Thereafter, recent investigations have rapidly uncovered diverse and essential functions of LKB1 in the developing and mature nervous system, such as migration, neurite morphogenesis, myelination and the maintenance of neural integrity, demonstrating that LKB1 is also a multifunctional master kinase in the nervous system. In this review article, we summarize the expanding knowledge about the functional aspects of LKB1 signaling in neural development and homeostasis.

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Section: Functions Of Lkb1 In Neural Developmentmentioning

confidence: 97%

Versatile Roles of LKB1 Kinase Signaling in Neural Development and Homeostasis

Kuwako

2018

Front. Mol. Neurosci.

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“…Similarly, overexpression of Akt3, Rheb, or Mtor containing activating mutations also causes cytomegaly, cytoarchitectural disorganization in the cortex, and seizures . Targeted KD of Strada causes FCD and cytomegaly in the mouse cortex but the Strada germline KO exhibits a perinatal lethal phenotype, so a seizure phenotype has not been yet reported.…”

Section: Epileptogenesis and Mtor‐gator Signalingmentioning

confidence: 99%

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

et al. 2019

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The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

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“…elegans , has been reported to be involved in axon specification in vivo (Asada et al, 2007 ; Barnes et al, 2007 ; Shelly et al, 2007 ). A pseudokinase Ste20-related kinase adaptor α (STRADα̣ can stabilize LKB1 (Veleva-Rotse et al, 2014 ), and LKB1 is activated by protein kinase A-dependent local phosphorylation on S431 in the trailing processes of newborn migrating neurons, followed by activation of the downstream kinases SAD-A and SAD-B, both of which are known to be essential for axon formation by phosphorylating Tau-1 (Kishi et al, 2005 ; Barnes et al, 2007 ). STRAD α has been identified as the gene responsible for the autosomal recessive neurodevelopmental disorder polyhydramnios, megalencephaly, and symptom epilepsy syndrome (PMSE), which is characterized by macrocephaly, craniofacial dismorphism, hypotonica, cognitive disability, and intrac epilepsy (Puffenberger et al, 2007 ).…”

Section: Multipolar Cell To Bipolar Cell Transitionmentioning

confidence: 99%

Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development

Ohtaka-Maruyama

Okado

2015

Front. Neurosci.

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Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.

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STRAD pseudokinases regulate axogenesis and LKB1 stability

Cited by 20 publications

References 49 publications

Versatile Roles of LKB1 Kinase Signaling in Neural Development and Homeostasis

Versatile Roles of LKB1 Kinase Signaling in Neural Development and Homeostasis

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development

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