A5043534898- PI3K/AKT/mTOR signaling in cancer
- Polyamine Metabolism and Applications
- Autophagy in Disease and Therapy
- Tuberous Sclerosis Complex Research
- Metabolism, Diabetes, and Cancer
- Cellular transport and secretion
- Mast cells and histamine
- Pancreatic function and diabetes
- Renal Diseases and Glomerulopathies
- Protein Kinase Regulation and GTPase Signaling
- Genetic and Kidney Cyst Diseases
- Microtubule and mitosis dynamics
- Adipose Tissue and Metabolism
- Ubiquitin and proteasome pathways
- Genetic Syndromes and Imprinting
- Endoplasmic Reticulum Stress and Disease
- Adipokines, Inflammation, and Metabolic Diseases
- RNA modifications and cancer
- Cancer-related Molecular Pathways
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Biomedical Research and Pathophysiology
- 14-3-3 protein interactions
- Wnt/β-catenin signaling in development and cancer
- Hedgehog Signaling Pathway Studies
- Histone Deacetylase Inhibitors Research
University of Michigan
2016-2025
Michigan Medicine
2024
Ann Arbor Center for Independent Living
2012-2023
Washtenaw Community College
2008-2022
Michigan United
2019-2021
Laboratoire d’immunologie intégrative du cancer
2009-2020
RELX Group (United States)
2016
Arkana Laboratories
2012
International Life Sciences Institute India
2012
Regional West Medical Center
2009
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2 . The and gene products form functional inhibit phosphorylation of S6K 4EBP1. These functions TSC1/TSC2 are likely mediated mTOR. Here we report that GTPase-activating protein (GAP) toward Rheb, Ras family GTPase. Rheb stimulates This function blocked rapamycin dominant-negative the mTOR plays an essential role regulation 4EBP1 response to nutrients cellular energy status. Our data demonstrate...
Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, deficiency associated elevated reactive oxygen species (ROS). ROS central role many physiological pathophysiological processes including inflammation chronic diseases such as atherosclerosis cancer, underscoring importance of pathways involved redox...
Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show LKB1 , the gene mutated in PJS, acts as a suppressor by activating TSC2 TSC. Like TSC2, inhibits phosphorylation of key translational regulators S6K 4EBP1. Furthermore, activates through AMP-dependent protein kinase (AMPK), indicating plays role cell growth regulation response to cellular energy levels. Our results...
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side Golgi apparatus, TOR-autophagy spatial coupling (TASCC), where (auto)lysosomes mTOR accumulated during Ras-induced senescence. recruitment TASCC was amino acid- Rag guanosine...
Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and 2 diabetics. Podocyte dysfunction postulated to be a critical event associated with proteinuria glomerulosclerosis glomerular diseases including DN. However, molecular mechanisms of podocyte development DN are not well understood. Here we have shown activity mTOR complex (mTORC1), kinase senses nutrient availability, was enhanced podocytes diabetic animals. Further, podocyte-specific mTORC1 activation...
Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining podocyte function, while dysregulation of facilitated diseases. Genetic deletion complex 1 (mTORC1) in mouse podocytes induced proteinuria progressive glomerulosclerosis. Furthermore, simultaneous both mTORC1 mTORC2 from aggravated the lesions,...
Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller. TOR exists two distinct complexes, termed TORC1 TORC2. Mammalian TORC2 has recently been shown to possess activity toward the C-terminal hydrophobic site Akt/PKB. Here, we report that Sin1 essential component but not TORC1, functions similarly Rictor, defining member TORC2, complex formation activity. Knockdown Sin1decreases Akt phosphorylation both Drosophila mammalian...
AMP-activated protein kinase (AMPK) senses energetic stress and, in turn, promotes catabolic and suppresses anabolic metabolism coordinately to restore energy balance. We found that a diverse array of AMPK activators increased mTOR complex 2 (mTORC2) signaling an AMPK-dependent manner cultured cells. Activation with the type diabetes drug metformin (GlucoPhage) also mTORC2 liver vivo primary hepatocytes manner. AMPK-mediated activation did not result from suppression mTORC1 thus reduced...
The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 regulate the translation 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, roles LARP1 in are controversial and its regulatory mTORC1-mediated remain unclear. Here we show that is a direct substrate Akt/S6K1. Deep sequencing LARP1-bound reveal non-phosphorylated interacts with both 5' 3'UTRs RP inhibits their translation. Importantly, phosphorylation by Akt/S6K1 dissociates it from 5'UTRs...
The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, healthy controls (HCs). Participants T2D obese had higher estimated glomerular filtration rates mesangial volumes than HCs. Ten participants been prescribed SGLT2i (T2Di[+]) 6 not (T2Di[-]). Transcriptional...
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either the tsc1 or tsc2 tumor suppressor gene. Recent studies have demonstrated that TSC2 displays GAP (GTPase-activating protein) activity specifically towards small G protein Rheb and inhibits its ability to stimulate mTOR signaling pathway. comprise unique pair of GTPase GAP, because has high basal GTP levels does not catalytic arginine finger found Ras-GAP. To investigate function signaling, we analyzed...
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an essential role in cell growth control. mTOR stimulates by phosphorylating p70 ribosomal S6 (S6K) and eukaryote initiation factor 4E-binding protein 1 (4EBP1). pathway regulated wide variety cellular signals, including mitogenic factors, nutrients, energy levels, stress conditions. Recent studies have proposed several mechanisms to explain how factors levels. However, little known as We observed two...
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs. Two genes responsible for the disease, TSC1 and TSC2, have been identified. The TSC2 proteins, also called hamartin tuberin, respectively, shown to regulate cell growth through inhibition of mammalian target rapamycin pathway. known stabilize forming a with which GTPase-activating protein Rheb small GTPase. We identified HERC1 as TSC2-interacting protein. 532-kDa E3...
Glucose transport is a highly regulated process and dependent on variety of signaling events. Glycogen synthase kinase-3 (GSK-3) has been implicated in various aspects the regulation glucose transport, but mechanisms by which GSK-3 activity affects uptake have not well defined. We report that basal glycogen regulates several cell types. Chronic inhibition (8-24 h) types, including vascular smooth muscle cells, resulted an approximately twofold increase due to similar protein expression...
Target of rapamycin (TOR) plays a central role in cell growth regulation by integrating signals from factors, nutrients, and cellular energy levels. TOR forms two distinct physical functional complexes, termed complex 1 (TORC1) 2 (TORC2). TORC1, which is sensitive to rapamycin, regulates translation growth, whereas TORC2, insensitive morphology growth. The Ras homology enriched brain (Rheb) small GTPase known be key upstream activator although the mechanism Rheb TORC1 activation remains...