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STRAD pseudokinases regulate axogenesis and LKB1 stability.

ABSTRACT: Neuronal polarization is an essential step of morphogenesis and connectivity in the developing brain. The serine/threonine kinase LKB1 is a key regulator of cell polarity, metabolism, tumorigenesis, and is required for axon formation. It is allosterically regulated by two related and evolutionarily conserved pseudokinases, STe20-Related ADapters (STRADs) ? and ?. The roles of STRAD? and STRAD? in the developing nervous system are not fully defined, nor is it known whether they serve distinct functions.We find that STRAD? is highly spliced and appears to be the primal STRAD paralog. We report that each STRAD is sufficient for axogenesis and promoting cell survival in the developing cortex. We also reveal a reciprocal protein-stabilizing relationship in vivo between LKB1 and STRAD?, whereby STRAD? specifically maintains LKB1 protein levels via cytoplasmic compartmentalization.We demonstrate a novel role for STRAD? in axogenesis and also show for the first time in vivo that STRAD?, but not STRAD?, is responsible for LKB1 protein stability.

SUBMITTER: Veleva-Rotse BO

PROVIDER: S-EPMC4016016 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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STRAD pseudokinases regulate axogenesis and LKB1 stability.

Veleva-Rotse Biliana O BO Smart James L JL Baas Annette F AF Edmonds Benjamin B Zhao Zi-ming ZM Brown Allyson A Klug Lillian R LR Hansen Kelly K Reilly Gabrielle G Gardner Alexandria P AP Subbiah Krishnaveni K Gaucher Eric A EA Clevers Hans H Barnes Anthony P AP

Neural development 20140304

<h4>Background</h4>Neuronal polarization is an essential step of morphogenesis and connectivity in the developing brain. The serine/threonine kinase LKB1 is a key regulator of cell polarity, metabolism, tumorigenesis, and is required for axon formation. It is allosterically regulated by two related and evolutionarily conserved pseudokinases, STe20-Related ADapters (STRADs) α and β. The roles of STRADα and STRADβ in the developing nervous system are not fully defined, nor is it known whether they ...[more]

PMID: 24594058

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Project description:The myocardium undergoes extensive metabolic and energetic remodeling during the progression of cardiac disease. Central to remodeling are changes in the adenine nucleotide pool. Fluctuations in these pools can activate AMP-activated protein kinase (AMPK), the central regulator of cellular energetics. Binding of AMP to AMPK not only allosterically activates AMPK but also promotes phosphorylation of AMPK by an upstream kinase complex, LKB1/Mo25/STRAD (liver kinase B 1, mouse protein 25, STE-related adaptor protein). AMPK phosphorylation by the LKB1 complex results in a substantial increase in AMPK activity. Molecular targeting by the LKB1 complex depends on subcellular localization and transcriptional expression. Yet, little is known about the ability of the LKB1 complex to modulate targeting of AMPK after activation. Accordingly, we hypothesized that differing stoichiometric ratios of LKB1 activator complex to AMPK would uniquely impact myofilament function. Demembranated rat cardiac trabeculae were incubated with varying ratios of the LKB1 complex to AMPK or the LKB1 complex alone. After incubation, we measured the Ca(2+) sensitivity of tension, rate constant for tension redevelopment, maximum tension generation, length-dependent activation, cooperativity, and sarcomeric protein phosphorylation status. We found that the Ca(2+) sensitivity of tension and cross-bridge dynamics were dependent on the LKB1 complex/AMPK ratio. We also found that the LKB1 complex desensitizes and suppresses myofilament function independently of AMPK. A phospho-proteomic analysis of myofilament proteins revealed site-specific changes in cardiac Troponin I (cTnI) phosphorylation, as well as a unique distribution of cTnI phosphospecies that were dependent on the LKB1 complex/ AMPK ratio. Fibers treated with the LKB1 complex alone did not alter cTnI phosphorylation or phosphospecies distribution. However, LKB1 complex treatment independent of AMPK increased phosphorylation of myosin-binding protein C. Therefore, we conclude that the LKB1/AMPK signaling axis is able to alter muscle function through multiple mechanisms.

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STRAD pseudokinases regulate axogenesis and LKB1 stability.

Publications

STRAD pseudokinases regulate axogenesis and LKB1 stability.

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