Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity
            <i>in vivo</i>

Hurov, Jonathan; Huang, Mei; White, Lynn S.; Lennerz, Jochen K.; Choi, Cheol Soo; Cho, You-Ree; Kim, Hyo-Jeong; Prior, Julie L.; Piwnica-Worms, David; Cantley, Lewis C.; Kim, Jason K.; Shulman, Gerald I.; Piwnica‐Worms, Helen

doi:10.1073/pnas.0701179104

Cited by 71 publications

(76 citation statements)

References 58 publications

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“…Recent studies have demonstrated that AMPK regulates tight junction assembly and cell polarity in mammalian cells and in Drosophila in a manner linked to the response to energy stress (28,51,52). Mouse knockouts of MARK2 show metabolic defects (19). Collectively, these data support the view that energy sensing and cell polarity may be broadly integrated under the control of LKB1-AMPK signaling.…”

supporting

confidence: 71%

“…The AMPK/MARK/SAD subfamily kinases can be activated by the Lkb1-mediated phosphorylation of a threonine residue in their activation loops (30). AMPKs, MARKs, and SADs are potential mediators of the Lkb1-dependent regulation of epithelial polarity, through their roles in the establishment of tight junctions and the regulation of tubulin dynamics (14,15,19,28,51,52). Western blotting analyses of PD1 pancreatic lysates demonstrated greatly reduced phosphorylation of AMPK, MARK2 and MARK3, and SAD-B in the p-Lkb1 pancreas.…”

Section: Resultsmentioning

confidence: 99%

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Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

Hezel

Gurumurthy

Granot³

et al. 2008

Molecular and Cellular Biology

137

119

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LKB1 is a key regulator of energy homeostasis through the activation of AMP-activated protein kinase (AMPK) and is functionally linked to vascular development, cell polarity, and tumor suppression. In humans, germ line LKB1 loss-of-function mutations cause Peutz-Jeghers syndrome (PJS), which is characterized by a predisposition to gastrointestinal neoplasms marked by a high risk of pancreatic cancer. To explore the developmental and physiological functions of Lkb1 in vivo, we examined the impact of conditional Lkb1 deletion in the pancreatic epithelium of the mouse. The Lkb1-deficient pancreas, although grossly normal at birth, demonstrates a defective acinar cell polarity, an abnormal cytoskeletal organization, a loss of tight junctions, and an inactivation of the AMPK/MARK/SAD family kinases. Rapid and progressive postnatal acinar cell degeneration and acinar-to-ductal metaplasia occur, culminating in marked pancreatic insufficiency and the development of pancreatic serous cystadenomas, a tumor type associated with PJS. Lkb1 deficiency also impacts the pancreas endocrine compartment, characterized by smaller and scattered islets and transient alterations in glucose control. These genetic studies provide in vivo evidence of a key role for LKB1 in the establishment of epithelial cell polarity that is vital for pancreatic acinar cell function and viability and for the suppression of neoplasia.LKB1 encodes an evolutionarily conserved serine/threonine kinase that is involved in the regulation of cellular responses to energy stress and in the establishment of cell polarity (1,3,23). In response to an increase in the AMP/ATP ratio, LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK), a key negative regulator of mTOR. Activation of the LKB1-AMPK axis results in a decrease in ATP-consuming processes and an increase in ATP production via inactivated mTOR, diminished fatty acid and glucose metabolism, and enhanced glucose transport. LKB1 also activates other members of the AMPK-related kinase subfamily including the microtubule affinity-regulating kinases 1 to 4 (MARK1, -2, -3 and -4) and the SAD/Brsk kinases (SAD-A and SAD-B) that induce cell polarity (30). Notably, LKB1 is required for the establishment of cell polarity in Drosophila melanogaster and Caenorhabditis elegans, as well as in cultured mammalian epithelial cells (2, 31, 48). Along similar lines, LKB1 and the SAD kinase define a pathway required for the polarization of neurons (6,43). Recent studies have demonstrated that AMPK regulates tight junction assembly and cell polarity in mammalian cells and in Drosophila in a manner linked to the response to energy stress (28, 51, 52). Mouse knockouts of MARK2 show metabolic defects (19). Collectively, these data support the view that energy sensing and cell polarity may be broadly integrated under the control of LKB1-AMPK signaling.In humans, germ line loss-of-function mutations of LKB1 are associated with Peutz-Jeghers syndrome (PJS), a disease characterized by benign gastrointestinal polyps (ham...

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supporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

Hezel

Gurumurthy

Granot³

et al. 2008

Molecular and Cellular Biology

137

119

View full text Add to dashboard Cite

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“…If a kinase directly phosphorylated their putative substrate, the kinase would never choose a cell type, hepatocytes, or model cells (HEK293), and regulate the cellular downstream cascades of the substrate in the same manner, which may deny that AMPK is the CRTC2 kinase in hepatocytes. However, it does not deny the contribution of AMPK to gluconeogenesis in hepatocytes (36), although we have to mention here that other AMPK family kinases, MARKs (37,38), may be capable of phosphorylating CRTC in cells (32,39).…”

Section: Discussionmentioning

confidence: 99%

Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes

Itoh

Sanosaka

Fuchino

et al. 2015

Journal of Biological Chemistry

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Background: Salt-inducible kinases (SIKs) are capable of suppressing gluconeogenic gene expression in hepatocytes when they are overexpressed. Results: However, enhanced gluconeogenic programs are observed only in SIK3-defective hepatocytes. Conclusion: SIK3 is the major kinase that down-regulates gluconeogenesis. Significance: The present study proposes that SIK3 could be a new target of diabetic care.

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“…The physiological functions of the MARK2 and MARK3 kinases have recently been studied using targeted gene knockout approaches in mice (5,6). Two independently derived mouse lines null for MARK2 have implicated this protein kinase in diverse physiological processes, including fertility (7), immune system homeostasis (8), learning and memory (9), and glucose homeostasis and energy metabolism (6).…”

mentioning

confidence: 99%

Inactivation of MARK4, an AMP-activated Protein Kinase (AMPK)-related Kinase, Leads to Insulin Hypersensitivity and Resistance to Diet-induced Obesity

Sun

Liang

Nie

et al. 2012

Journal of Biological Chemistry

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Background: MARK4 is a member of the AMPK-related kinase family whose biological function remains elusive. Results: Using mice with targeted deletion of mark4, we identified a key role of the kinase in regulating glucose and energy homeostasis. Conclusion: MARK4 is required for energy homeostasis by regulating satiety and the metabolic rate in rodents. Significance: These data provide a key insight for targeting MARK4 for the treatment of obesity.

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Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo

Cited by 71 publications

References 58 publications

Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes

Inactivation of MARK4, an AMP-activated Protein Kinase (AMPK)-related Kinase, Leads to Insulin Hypersensitivity and Resistance to Diet-induced Obesity

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