New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

Загорска, Анна; Deák, Mária; Campbell, David G.; Banerjee, Sourav; Hirano, Mariko; Aizawa, Shinichi; Prescott, Alan R.; Alessi, Dario R.

doi:10.1126/scisignal.2000616

Cited by 146 publications

(226 citation statements)

References 53 publications

(66 reference statements)

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“…Previous studies revealed that AMPK regulates tight junction assembly (46,47), possibly by affecting the actin cytoskeleton through phosphorylation of myosin regulatory light chain (48). Polarity effects of LKB1 have also been associated with PAR proteins, AMPK-related kinases NUAK1/2, which are activated by LKB1, and control of cell adhesion by regulating myosin phosphatase complexes (49). In addition, AMPK may regulate canalicular network formation through the apical recycling pathway.…”

Section: Discussionmentioning

confidence: 99%

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Wakabayashi

Lippincott‐Schwartz

et al. 2011

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

120

115

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This study describes a unique function of taurocholate in bile canalicular formation involving signaling through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway. In rat hepatocyte sandwich cultures, polarization was manifested by sequential progression of bile canaliculi from small structures to a fully branched network. Taurocholate accelerated canalicular network formation and concomitantly increased cAMP, which were prevented by adenyl cyclase inhibitor. The cAMP-dependent PKA inhibitor did not prevent the taurocholate effect. In contrast, activation of Epac, another cAMP downstream kinase, accelerated canalicular network formation similar to the effect of taurocholate. Inhibition of Epac downstream targets, Rap1 and MEK, blocked the taurocholate effect. Taurocholate rapidly activated MEK, LKB1, and AMPK, which were prevented by inhibition of adenyl cyclase or MEK. Our previous study showed that activated-LKB1 and AMPK participate in canalicular network formation. Linkage between bile acid synthesis, hepatocyte polarization, and regulation of energy metabolism is likely important in normal hepatocyte development and disease.primary hepatocytes | occludin | P-glycoprotein H epatocytes, the major epithelial cells in the liver, are polarized. Tight junction proteins, including occludin, claudin, and ZO-1, seal the canalicular lumen, thereby separating apical and basolateral membrane domains and forming the bile canaliculus (1). Polarization is essential for biliary secretion. The mechanisms of polarization are complex and include cytoskeletal, tight junctional, and intracellular trafficking components (2-5). Loss of polarity causes bile secretory failure (cholestasis) and liver damage (6).Bile acids are synthesized from cholesterol in hepatocytes, secreted by ABCB11 (Bsep) into the bile canaliculus, and then mostly absorbed into the enterohepatic circulation (7). The major bile acids in mammals are tauro or glycine conjugates of cholic, deoxycholic, and chenodeoxycholic acids (8). In addition to their traditional function in emulsification of dietary fat (8), recent studies reveal that bile acids function as signaling molecules (9), which increase calcium mobilization (10) and cellular cAMP (9); translocate and activate protein kinase C (11), nuclear farnesoid X receptor (FXR), and pregnane X receptors (PXR) (7, 9); activate PI3K/AKT/glycogen synthase kinase 3 (GSK3) (12); and enhance liver regeneration (13).During embryonic development, early fetal hepatocytes are not polarized (14-16). In fetal mice and rats, infrequent small canaliculi are present, but do not attain an adult appearance until several days postpartum (17). Bile acid synthesis, turnover, and secretion are sparse in fetal liver, and rapidly increase postnatally (18,19), concomitant with hepatocyte polarization and development of a branched canalicular network. Based on these events, we postulated that bile acids may regulate hepatocyte polarization and canalicular formation. Using collagen sandwich cultures of rat primary hepatocytes, we confirmed this hy...

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Section: Discussionmentioning

confidence: 99%

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Wakabayashi

Lippincott‐Schwartz

et al. 2011

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

120

115

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“…This reported effect on paramyosin phosphorylation might occur because paramyosin is an UNC-82 substrate, or through an indirect mechanism. The mammalian UNC-82 ortholog ARK5/NUAK1 increases myosin light chain phosphorylation in human embryonic kidney cells by phosphorylating and inactivating a myosin phosphatase (Zagórska et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Double knockouts of these orthologs have not been studied in mammalian muscle; these mutants arrest with defects in embryonic morphogenesis (Ohmura et al 2012). Interestingly, in human kidney cells, ARK5 has been shown to regulate nonmuscle myosin light chain phosphorylation (Zagórska et al 2010). We propose that the UNC-82 kinase associates stoichiometrically, directly or indirectly, with recently synthesized paramyosin to promote proper assembly of paramyosin into the thick filament.…”

mentioning

confidence: 95%

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle of Caenorhabditis elegans

Schiller¹,

Duchesneau²,

Lane³

et al. 2017

Genetics

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We study the mechanisms that guide the formation and maintenance of the highly ordered actin-myosin cytoskeleton in striated muscle. The UNC-82 kinase of Caenorhabditis elegans is orthologous to mammalian kinases ARK5/NUAK1 and SNARK/ NUAK2. UNC-82 localizes to the M-line, and is required for proper organization of thick filaments, but its substrate and mechanism of action are unknown. Antibody staining of three mutants with missense mutations in the UNC-82 catalytic domain revealed muscle structure that is less disorganized than in the null unc-82(0), but contained distinctive ectopic accumulations not found in unc-82(0). These accumulations contain paramyosin and myosin B, but lack myosin A and myosin A-associated proteins, as well as proteins of the integrin-associated complex. Fluorescently tagged missense mutant protein UNC-82 E424K localized normally in wild type; however, in unc-82(0), the tagged protein was found in the ectopic accumulations, which we also show to label with recently synthesized paramyosin. Recruitment of wild-type UNC-82::GFP to aggregates of differing protein composition in five muscle-affecting mutants revealed that colocalization of UNC-82 and paramyosin does not require UNC-96, UNC-98/ZnF, UNC-89/obscurin, CSN-5, myosin A, or myosin B individually. Dosage effects in paramyosin mutants suggest that UNC-82 acts as part of a complex, in which its stoichiometric relationship with paramyosin is critical. UNC-82 dosage affects muscle organization in the absence of paramyosin, perhaps through myosin B. We present evidence that the interaction of UNC-98/ZnF with myosin A is independent of UNC-82, and that UNC-82 acts upstream of UNC-98/ZnF in a pathway that organizes paramyosin during thick filament assembly.

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“…Recently, Vallenius et al [33] have shown that an association between AMP kinase-related kinase SNARK and myosin phosphatase Rho-interacting protein (MRIP) reveals a novel mechanism for regulation of actin stress fibers via activation of MLCP (myosin light chain phosphatase). Moreover, new roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion have been shown [34].…”

Section: Activation Of Protein Kinase Snark During Muscle Contractionmentioning

confidence: 99%

“…Moreover, there is data that the LKB1-NUAK pathway plays important role in controlling myosin phosphatase complexes and cell adhesion [34]. NUAK1 regulates ploidy and senescence; cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects [17].…”

Section: Snf1-like Kinase 1 (Nuak1) Amp-activated Protein Kinase Fammentioning

confidence: 99%

SNF1/AMP-Activated Protein Kinases: Genes, Expression and Biological Role

Minchenko¹,

Minchenko²

2012

Protein Kinases

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New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

Cited by 146 publications

References 53 publications

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle of Caenorhabditis elegans

SNF1/AMP-Activated Protein Kinases: Genes, Expression and Biological Role

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