Targeting the phosphatidylinositol 3-kinase pathway in airway smooth muscle: rationale and promise.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in regulating cell growth, proliferation, survival, and motility. Structural alterations, e.g. airway remodeling, in asthma and chronic obstructive pulmonary disease (COPD) are associated with increased airway smooth muscle (ASM) cell growth and proliferation due to the frequent stimulation of ASM by inflammatory mediators, contractile agonists, and growth factors. The critical role of the PI3K signaling pathway in regulating ASM cell growth and proliferation is well established. However, recent discovery of the tumor suppressor proteins tuberous sclerosis complex 1 (TSC1) and TSC2, also known as hamartin and tuberin, as downstream effectors of PI3K and upstream regulators of the mammalian target of rapamycin (mTOR) and S6 kinase 1(S6K1) shed a new light on the PI3K signaling cascade in regulating cell growth and proliferation. The activity of TSC1/TSC2 is regulated by growth factors, nutrients, and energy; thus, TSC1/TSC2 serves as a signaling module for protein translational regulation, cell cycle progression, and cell size, which are key events controlling cell growth and proliferation. This article highlights the potential contribution of the PI3K-TSC1/TSC2-mTOR/S6K1 pathway in smooth muscle remodeling. Pharmacologic manipulation of this signaling pathway could have a major impact on treatment of asthma and COPD.
Krymskaya
Vera P
VP
Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-3403, USA. krymskay@mail.med.upenn.edu
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
D000081082:Phosphoinositide-3 Kinase Inhibitors; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D051059:PTEN Phosphohydrolase