Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA. Electronic address: mccubreyj@ecu.edu.
James A
JA
McCubrey
Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
Dariusz
D
Rakus
Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
Agnieszka
A
Gizak
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
Linda S
LS
Steelman
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
Steve L
SL
Abrams
Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA.
Kvin
K
Lertpiriyapong
Department of Surgery, Brody School of Medicine at East Carolina University, USA.
Timothy L
TL
Fitzgerald
Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, USA.
Li V
LV
Yang
Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
Giuseppe
G
Montalto
Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
Melchiorre
M
Cervello
Department of Bio-medical Sciences, University of Catania, Catania, Italy.
Massimo
M
Libra
Department of Bio-medical Sciences, University of Catania, Catania, Italy.
Ferdinando
F
Nicoletti
Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy.
Aurora
A
Scalisi
Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy.
Francesco
F
Torino
Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section - Policlinico "G. Martino" - University of Messina, Messina 98125, Italy.
Concettina
C
Fenga
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Luca M
LM
Neri
Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
Sandra
S
Marmiroli
Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
Lucio
L
Cocco
Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
Alberto M
AM
Martelli
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; D053823:Hedgehog Proteins; D035683:MicroRNAs; D051880:Receptors, Notch; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3
Akt; GSK-3; Hedgehog; Notch; PI3K; Targeted therapy; Therapy resistance; Wnt/beta-catenin; mTOR