Review
Biochemistry & Molecular Biology
Nicola J. Darling, Philip Cohen
Summary: The salt-inducible kinases (SIKs) are closely related to AMP-activated protein kinase (AMPK) and require phosphorylation by LKB1 for activation. They are phosphorylated by PKA to be inactivated. The main substrates of SIKs are CRTCs and Class 2a HDACs, and their regulation by SIKs influences various physiological processes. The reversible regulation of these substrates by SIKs highlights their potential in therapeutic interventions for diseases.
BIOCHEMICAL JOURNAL
(2021)
Review
Physiology
Aarti Jagannath, Lewis Taylor, Yining Ru, Zeinab Wakaf, Kayomavua Akpobaro, Sridhar Vasudevan, Russell G. Foster
Summary: Salt-inducible kinases (SIKs) are a family of serine-threonine kinases that regulate multiple aspects of physiology. They convey signals about the cellular environment to reprogram transcriptional and posttranscriptional processes. SIKs have been shown to regulate metabolic responses, inflammation, immune responses, and sleep/circadian rhythms. This article summarizes the molecular mechanisms of SIKs in controlling various physiological domains, particularly in the context of sleep and circadian rhythm regulation.
PHYSIOLOGICAL REVIEWS
(2023)
Article
Oncology
Alifiani Bonita Hartono, Hong-Jun Kang, Lawrence Shi, Whitney Phipps, Nathan Ungerleider, Alexandra Giardina, WeiPing Chen, Lee Spraggon, Romel Somwar, Krzysztof Moroz, David H. Drewry, Matthew E. Burow, Erik Flemington, Marc Ladanyi, Sean Bong Lee
Summary: Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive malignant cancer caused by a chromosomal translocation. The study identified SIK1 as a direct target of the oncogenic transcription factor EWSR1-WT1, and depletion of SIK1 inhibited tumor cell growth and DNA replication. Combined inhibition of SIK1 and CHEK1 showed enhanced cytotoxicity in DSRCT cells.
Article
Multidisciplinary Sciences
Zhihui Fong, Caoimhin S. Griffin, Roddy J. Large, Mark A. Hollywood, Keith D. Thornbury, Gerard P. Sergeant
Summary: P2X1 receptors are inhibited by EPAC activators, while P2X2 current amplitudes are enhanced. PKA activators have no effect on P2X1 receptors but inhibit P2X2 receptors. The inhibitory effects of EPAC on P2X1 receptors can be prevented through mutations and an inhibitor of Rac1.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Meriam Nefla, Nicola J. Darling, Manuel van Gijsel Bonnello, Philip Cohen, J. Simon C. Arthur
Summary: Salt Inducible Kinases 2 (SIK2) and 3 (SIK3) play important roles in thymic T cell development, with their loss leading to decreased numbers of peripheral T cells and defects in negative and/or positive selection in the thymus.
SCIENTIFIC REPORTS
(2021)
Article
Behavioral Sciences
Lixuan Peng, Cai Li, Xiaohan Tang, Yuyan Xiang, Yang Xu, Wenyu Cao, Huamao Zhou, Suyun Li
Summary: This study investigated the effect of blocking SIKs on seizures and found that SIK1 plays a regulatory role in neuronal hyperactivity and seizure behavior. Targeting SIK1 through the development of selective inhibitors may help reduce epilepsy progression.
BRAIN AND BEHAVIOR
(2023)
Article
Biochemistry & Molecular Biology
Kim Chi Vo, Liberta Ruga, Olympia Ekaterini Psathaki, Rico Franzkoch, Ute Distler, Stefan Tenzer, Michael Hensel, Peter Hegemann, Nishith Gupta
Summary: This study reveals the catalytic function, subcellular localization, and drug inhibition of key phosphodiesterases in Toxoplasma gondii, highlighting the unexpected plasticity and therapeutic potential of cyclic nucleotide signaling in the parasite.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Review
Pharmacology & Pharmacy
Aduragbemi A. Faniyi, Michael J. Hughes, Aaron Scott, Kylie B. R. Belchamber, Elizabeth Sapey
Summary: Lung diseases have a greater impact on elderly individuals due to the vulnerability of the lungs to age-related changes and inflammation. Despite different causes, the burden of aging and inflammation exacerbates seemingly unrelated pathologies, but also offers a common route to treatment.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Neale Harrison, Chek Ziu Koo, Michael G. Tomlinson
Summary: ADAM10 acts as a molecular scissor by cleaving membrane protein substrates through ectodomain shedding, interacting with various substrates and particularly with the TspanC8 subgroup of tetraspanins. Recent studies suggest that different TspanC8/ADAM10 complexes have distinct substrates, offering therapeutic potential for diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Konica Porwal, Subhashis Pal, Sudha Bhagwati, Mohd Imran Siddiqi, Naibedya Chattopadhyay
Summary: This review critically discusses the effects of PDE inhibitors in bone cells, from cellular signaling to various preclinical models evaluating bone formation mechanisms. Pentoxifylline and rolipram are the most studied inhibitors with osteogenic effects, suggesting their potential for post-menopausal osteoporosis treatment through therapeutic repurposing. These two inhibitors are treated as prototypical osteogenic PDEs to predict new chemotypes for drug design based on the structural biology of PDEs.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Helene Borrmann, Dini Ismed, Anna E. Kliszczak, Persephone Borrow, Sridhar Vasudevan, Aarti Jagannath, Xiaodong Zhuang, Jane A. McKeating
Summary: Human immunodeficiency virus type 1 (HIV-1) poses a significant global health burden, and eradicating latent virus infection is a major challenge. The circadian clock, an internal timing system, regulates HIV-1 replication. Salt inducible kinases (SIK) contribute to this regulation, and inhibiting SIKs disrupts the cellular clock and reduces rhythmic HIV-1 replication. This study demonstrates the role of SIKs in regulating HIV-1 replication and latency reactivation, providing insights for understanding and targeting latent HIV-1 infection.
JOURNAL OF GENERAL VIROLOGY
(2023)
Review
Endocrinology & Metabolism
Stepan Gambaryan, Sanika Mohagaonkar, Viacheslav O. Nikolaev
Summary: The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in blood volume and blood pressure regulation, and its dysfunction is associated with cardiovascular and renal diseases. Cyclic nucleotides and phosphodiesterases are the main regulators of this system, controlling the expression and activity of renin and aldosterone. This review summarizes the known mechanisms by which cyclic nucleotides and phosphodiesterases regulate the expression of renin gene, secretion of renin granules, and production of aldosterone, as well as highlighting some unanswered questions for future research.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Pharmacology & Pharmacy
Arun Samidurai, Lei Xi, Anindita Das, Audra N. Iness, Navin G. Vigneshwar, Pin-Lan Li, Dinender K. Singla, Sakthivel Muniyan, Surinder K. Batra, Rakesh C. Kukreja
Summary: Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that regulate the spatial and temporal relationship of second messenger signaling in the cellular system. The PDE1 sub-family consists of three subtypes with different affinities for cAMP and cGMP, and their catalytic activity is stimulated by binding to Ca2+/calmodulin, playing a critical role in various diseases.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Akihisa Kato, Serina Ng, Amalraj Thangasamy, Haiyong Han, Wendi Zhou, Stephane Raeppel, Michael Fallon, Sushovan Guha, Sudhakar Ammanamanchi
Summary: High expression of the RON tyrosine kinase receptor has been identified as a predictor of poor prognosis in pancreatic cancer. RON directly regulates HIF-1 alpha, a key driver of genes involved in cancer cell invasion and metastasis. Inhibition of RON could be a potential novel therapeutic target for cancers, including triple-negative breast cancer.
MOLECULAR CARCINOGENESIS
(2021)
Article
Pharmacology & Pharmacy
Hiroko Shiraki, Shigeru Tanaka, Yun Guo, Kana Harada, Izumi Hide, Tomoharu Yasuda, Norio Sakai
Summary: GPR3 is immediately induced by T cell stimulation and plays an important role in suppressing effector T cell activation.
JOURNAL OF PHARMACOLOGICAL SCIENCES
(2022)
Article
Endocrinology & Metabolism
Severine Olivier, Camille Pochard, Hanna Diounou, Vanessa Castillo, Jordane Divoux, Joshua Alcantara, Jocelyne Leclerc, Sandra Guilmeau, Camille Huet, Wafa Charifi, Thibault V. Varin, Noemie Daniel, Marc Foretz, Michel Neunlist, Benoit L. Salomon, Pradipta Ghosh, Andre Marette, Malvyne Rolli-Derkinderen, Benoit Viollet
Summary: Intestinal AMPK plays a significant role in maintaining the integrity of distal colon IEB, but its function in regulating glucose homeostasis is limited.
MOLECULAR METABOLISM
(2021)
Article
Biology
Cheng-Chia Tang, Christian D. Castro Andrade, Maureen J. O'Meara, Sung-Hee Yoon, Tadatoshi Sato, Daniel J. Brooks, Mary L. Bouxsein, Janaina da Silva Martins, Jinhua Wang, Nathanael S. Gray, Barbara Misof, Paul Roschger, Stephane Boulin, Klaus Klaushofer, Annegreet Velduis-Vlug, Yosta Vegting, Clifford J. Rosen, Daniel O'Connell, Thomas B. Sundberg, Ramnik J. Xavier, Peter Ung, Avner Schlessinger, Henry M. Kronenberg, Rebecca Berdeaux, Marc Foretz, Marc N. Wein
Summary: The study found that the multi-kinase inhibitor YKL-05-099 may be a promising new class of bone anabolic agents that increase bone formation without increasing bone resorption, potentially overcoming limitations of current osteoporosis therapies.
Article
Oncology
Yajing Gao, Pekka Paivinen, Sushil Tripathi, Eva Domenech-Moreno, Iris P. L. Wong, Kari Vaahtomeri, Ashwini S. Nagaraj, Sarang S. Talwelkar, Marc Foretz, Emmy W. Verschuren, Benoit Viollet, Yan Yan, Tomi P. Makela
Summary: This study reveals that in LKB1-mutant LUAD, inactivation of AMPK leads to immune evasion, attenuated antigen presentation, and the formation of an immune suppressive tumor microenvironment.
CLINICAL CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Marie Octave, Laurence Pirotton, Audrey Ginion, Valentine Robaux, Sophie Lepropre, Jerome Ambroise, Caroline Bouzin, Bruno Guigas, Martin Giera, Marc Foretz, Luc Bertrand, Christophe Beauloye, Sandrine Horman
Summary: Inhibition of ACC and HDAC6 increases tubulin acetylation levels in platelets, affecting platelet aggregation independently of lipid content. This impact is associated with downregulation of the Rac1/PAK2 signaling pathway, unrelated to actin cytoskeleton.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Medicine, Research & Experimental
Severine Olivier, Hanna Diounou, Marc Foretz, Sandra Guilmeau, Noemie Daniel, Andre Marette, Malvyne Rolli-Derkinderen, Benoit Viollet
M S-MEDECINE SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Nuria Pescador, Vera Francisco, Patricia Vazquez, Eva Maria Esquinas, Cristina Gonzalez-Paramos, M. Pilar Valdecantos, Irma Garcia-Martinez, Andres A. Urrutia, Laura Ruiz, Carmen Escalona-Garrido, Marc Foretz, Benoit Viollet, Miguel Angel Fernandez-Moreno, Alfonso L. Calle-Pascual, Maria Jesus Obregon, Julian Aragones, Angela M. Valverde
Summary: Metformin impacts macrophages by inhibiting a HIF1 alpha-dependent proinflammatory program, leading to secondary beneficial effects on insulin-mediated glucose uptake and beta-adrenergic responses in brown adipocytes.
Article
Cell Biology
Severine Olivier, Hanna Diounou, Camille Pochard, Lisa Frechin, Emilie Durieu, Marc Foretz, Michel Neunlist, Malvyne Rolli-Derkinderen, Benoit Viollet
Summary: Dysfunctions in the intestinal barrier are commonly observed in inflammatory bowel disease (IBD) and the AMP-activated protein kinase (AMPK) plays a key role in the stabilization and assembly of tight junctions. This study investigated the contribution of intestinal epithelial AMPK to acute colitis and found that its deletion delayed intestinal injury repair and impaired barrier function. Metformin administration improved intestinal repair capacity independently of AMPK. These findings highlight the importance of AMPK in regulating mucosal repair and suggest the therapeutic potential of metformin in supporting the repair of injured intestinal epithelium.
Article
Cell Biology
Malgorzata Tokarska-Schlattner, Laurence Kay, Pascale Perret, Raffaella Isola, Stephane Attia, Frederic Lamarche, Cindy Tellier, Cecile Cottet-Rousselle, Amjad Uneisi, Isabelle Hininger-Favier, Marc Foretz, Herve Dubouchaud, Catherine Ghezzi, Christian Zuppinger, Benoit Viollet, Uwe Schlattner
Summary: AMPK, a key regulator of energy homeostasis, plays important roles in maintaining cardiac function under increased workload conditions. Deletion of AMPK genes in cardiomyocytes did not affect heart function under physiological conditions, but led to alterations in response to increased workload. AMPK deletion also resulted in decreased basal metabolic rate and locomotor activity, along with changes in cardiac mitochondrial function and bioenergetics.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Obstetrics & Gynecology
Pascal Froment, Ingrid Plotton, Cecilia Giulivi, Stephane Fabre, Rita Khoueiry, Nizar Mourad, Sandrine Horman, Christelle Rame, Charlene Rouillon, Jeremy Grandhaye, Yves Bigot, Claire Chevaleyre, Remy Le Guevel, Patricia Mallegol, Ramaroson Andriantsitohaina, Fabrice Guerif, Jerome Tamburini, Benoit Viollet, Marc Foretz, Joelle Dupont
Summary: The lack of alpha 1AMPK in granulosa cells impacts various biological processes and leads to a hyperandrogenic response.
HUMAN REPRODUCTION
(2022)
Article
Medicine, Research & Experimental
Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young
Summary: AMPK plays an essential role in maintaining homeostasis in the atria by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.
Article
Multidisciplinary Sciences
Annie Lee, Chandana Kondapalli, Daniel M. Virga, Tommy L. Lewis, So Yeon Koo, Archana Ashok, Georges Mairet-Coello, Sebastien Herzig, Marc Foretz, Benoit Viollet, Reuben Shaw, Andrew Sproul, Franck Polleux
Summary: This study reveals that soluble Amyloid-beta 1-42 oligomers (A beta 42o) trigger the loss of excitatory synapses in early Alzheimer's disease, prior to the formation of insoluble amyloid plaques. The researchers also found that A beta 42o leads to structural remodeling of mitochondria in specific regions and mediates synaptic loss through certain signaling pathways.
NATURE COMMUNICATIONS
(2022)
Article
Nutrition & Dietetics
Tristan Chalvon-Demersay, Claire Gaudichon, Joanna Moro, Patrick C. Even, Nadezda Khodorova, Julien Piedcoq, Benoit Viollet, Julien Averous, Anne-Catherine Maurin, Daniel Tome, Marc Foretz, Pierre Fafournoux, Dalila Azzout-Marniche
Summary: This study investigated the contribution of liver AMPK and GCN2 to the adaptation to high protein intake and found that they were not involved in this adaptation during the postprandial period.
EUROPEAN JOURNAL OF NUTRITION
(2023)
Article
Multidisciplinary Sciences
Javier Moral-Sanz, Sophronia A. Lewis, Sandy MacMillan, Marco Meloni, Heather McClafferty, Benoit Viollet, Marc Foretz, Jorge del-Pozo, A. Mark Evans
Summary: This study shows that deficiency of AMPK-alpha 1/alpha 2 in smooth muscles can cause persistent pulmonary hypertension in newborns. The findings provide important insights into the mechanism of pulmonary hypertension.
NATURE COMMUNICATIONS
(2022)
Article
Endocrinology & Metabolism
Iain R. Phair, Raid B. Nisr, Andrew J. M. Howden, Magdalena Sovakova, Noor Alqurashi, Marc Foretz, Douglas Lamont, Benoit Viollet, Graham Rena
Summary: This study demonstrates the integration of metabolite and kinase-based immunometabolic control in macrophages through the activation of AMP kinase. The deletion of AMPKa1 leads to a striking polarization of M1 macrophages upon LPS stimulation, along with increased expression of rate-limiting enzymes involved in various metabolic pathways.
MOLECULAR METABOLISM
(2022)
Article
Gastroenterology & Hepatology
Pascale Gluais-Dagorn, Marc Foretz, Gregory R. Steinberg, Battsetseg Batchuluun, Anna Zawistowska-Deniziak, Joost M. Lambooij, Bruno Guigas, David Carling, Pierre-Axel Monternier, David E. Moller, Sebastien Bolze, Sophie Hallakou-Bozec
Summary: The study demonstrates that direct activation of AMPK can improve all core components of NASH and alleviate related hyperglycemia, dyslipidemia, and systemic inflammation. Additionally, novel properties of direct AMPK activation were revealed, including improved insulin resistance and direct suppression of inflammation and fibrogenesis. These findings suggest the potential for direct AMPK activation as an effective treatment for patients with NASH, with effects also observed in human cells.
HEPATOLOGY COMMUNICATIONS
(2022)
