Skip to main content
SpringerLink
Log in

Implications of Phosphoinositide 3-Kinase (PI3K) Signalling in Cellular and Molecular Mechanisms of Respiratory Diseases

  • Chapter
  • First Online:
Targeting Cellular Signalling Pathways in Lung Diseases

  • 1006 Accesses

Abstract

Phosphoinositide 3-kinases (PI3Ks) are the central modulators of different cellular signalling pathways and play an important role in cell survival, proliferation, growth, metabolism, cell polarity, and activation of various immune cells, to mention a few. PI3Ks are classified into three main categories based on their structure and substrate specificity. In mammals and higher eukaryotes, there exist four isoforms of class I PI3K (PI3Kα, β, γ, δ), three isoforms of class II PI3K (PI3KC2α, C2β, C2γ), and a single class III PI3K. These isoforms have overlapping functions, but the stimulation for specific receptors required for their activation is also different. PI3Ks regulate a plethora of signalling cascades that are involved in pathway members which are involved in various physiological processes such as ROS generation, mast cell activation, neutrophil migration, etc. These events eventually lead to inflammation in various respiratory diseases like chronic obstructive pulmonary disease, asthma, emphysema, cystic fibrosis, etc. PI3K signalling has also been reported to be involved in SARS-CoV-2-mediated pneumonia in the lungs. Nowadays, inhibition of various members of PI3K pathway is the leading approach for the treatment of respiratory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Marwick J, Chung KF, Adcock I (2010) Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease. Ther Adv Respir Dis 4(1):19–34

    Article  PubMed  Google Scholar 

  2. Lugogo N, Kraft M (2006) Epidemiology of asthma. Clin Chest Med 27(1):1–15

    Article  PubMed  Google Scholar 

  3. Medina-Tato D, Ward S, Watson M (2007) Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology 121(4):448–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cantley L (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657

    Article  CAS  PubMed  Google Scholar 

  5. Vanhaesebroeck B, Stephens L, Hawkins P (2012) PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 13(3):195–203

    Article  CAS  PubMed  Google Scholar 

  6. Vanhaesebroeck B, Vogt P, Rommel C (2010) PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 347:1–19

    Google Scholar 

  7. Martini M, De Santis M, Braccini L, Gulluni F, Hirsch E (2014) PI3K/AKT signalling pathway and cancer: an updated review. Ann Med 46(6):372–383

    Article  CAS  PubMed  Google Scholar 

  8. Bilanges B, Posor Y, Vanhaesebroeck B (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20(9):515–534

    Article  CAS  PubMed  Google Scholar 

  9. Carracedo A, Pandolfi P (2008) The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene 27(41):5527–5541

    Article  CAS  PubMed  Google Scholar 

  10. Castellano E, Downward J (2011) RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2(3):261–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fruman D, Chiu H, Hopkins B, Bagrodia S, Cantley L, Abraham R (2017) The PI3K pathway in human disease. Cell 170(4):605–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gulluni F, De Santis M, Margaria J, Martini M, Hirsch E (2019) Class II PI3K functions in cell biology and disease. Trends Cell Biol 29(4):339–359

    Article  CAS  PubMed  Google Scholar 

  13. Mruk D, Cheng C (2010) The myotubularin family of lipid phosphatases in disease and in spermatogenesis. Biochem J 433(2):253–262

    Article  CAS  Google Scholar 

  14. Hurley J, Young L (2017) Mechanisms of autophagy initiation. Annu Rev Biochem 86(1):225–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jaber N, Mohd-Naim N, Wang Z, DeLeon J, Kim S, Zhong H, Sheshadri N, Dou Z, Edinger A, Du G, Braga V, Zong W (2016) Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus. J Cell Sci 129(23):4424–4435

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ornatowski W, Lu Q, Yegambaram M, Garcia A, Zemskov E, Maltepe E, Fineman J, Wang T, Black S (2020) Complex interplay between autophagy and oxidative stress in the development of pulmonary disease. Redox Biol 36:101679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lemmon M, Schlessinger J (2010) Cell signalling by receptor tyrosine kinases. Cell 141(7):1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jeong J, Kim J, Kim S, Lee Y (2019) Defining bronchial asthma with phosphoinositide 3-kinase delta activation: towards endotype-driven management. Int J Mol Sci 20(14):3525

    Article  CAS  PubMed Central  Google Scholar 

  19. Barnes P (2017) Cellular and molecular mechanisms of asthma and COPD. Clin Sci 131(13):1541–1558

    Article  CAS  Google Scholar 

  20. Pelaia G, Renda T, Gallelli L, Vatrella A, Busceti M, Agati S, Caputi M, Cazzola M, Maselli R, Marsico S (2008) Molecular mechanisms underlying airway smooth muscle contraction and proliferation: implications for asthma. Respir Med 102(8):1173–1181

    Article  PubMed  Google Scholar 

  21. Szymczak I, Wieczfinska J, Pawliczak R (2016) Molecular background of miRNA role in asthma and COPD: an updated insight. Biomed Res Int 2016:1–10

    Google Scholar 

  22. Shao Y, Chong L, Lin P, Li H, Zhu L, Wu Q, Li C (2018) MicroRNA-133a alleviates airway remodeling in asthma through PI3K/AKT/mTOR signalling pathway by targeting IGF1R. J Cell Physiol 234(4):4068–4080

    Article  PubMed  CAS  Google Scholar 

  23. Dong X, Zhong N, Fang Y, Cai Q, Lu M, Lu Q (2018) MicroRNA 27b-3p modulates SYK in pediatric asthma induced by dust mites. Front Pediatr 6:301

    Article  PubMed  PubMed Central  Google Scholar 

  24. Liu Y, Miao Y, Gao X, Wang Y, Wang H, Zheng Y, Zhao Z (2018) MicroRNA-200a affects the proliferation of airway smooth muscle cells and airway remodeling by targeting FOXC1 via the PI3K/AKT signalling pathway in ovalbumin-induced asthmatic mice. Cell Physiol Biochem 50(6):2365–2389

    Article  CAS  PubMed  Google Scholar 

  25. Heffler E, Allegra A, Pioggia G, Picardi G, Musolino C, Gangemi S (2017) MicroRNA profiling in asthma: potential biomarkers and therapeutic targets. Am J Respir Cell Mol Biol 57(6):642–650

    Article  CAS  PubMed  Google Scholar 

  26. Chen S, Zhang Z, Chen L, Zhang J (2019) miRNA 101 3p.1 as an independent diagnostic biomarker aggravates chronic obstructive pulmonary disease via activation of the EGFR/PI3K/AKT signalling pathway. Mol Med Rep 20:4293–4302

    CAS  PubMed  Google Scholar 

  27. Baker J, Vuppusetty C, Colley T, Papaioannou A, Fenwick P, Donnelly L, Ito K, Barnes P (2016) Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. Sci Rep 6(1):35871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Forbes L, Kapetanakis V, Rudnicka A, Cook D, Bush T, Stedman J, Whincup P, Strachan D, Anderson H (2009) Chronic exposure to outdoor air pollution and lung function in adults. Thorax 64(8):657–663

    Article  CAS  PubMed  Google Scholar 

  29. Wells A, Woods A, Hilleman D, Malesker M (2019) Alpha-1 antitrypsin replacement in patients with COPD. P T 44(7):412–415

    PubMed  PubMed Central  Google Scholar 

  30. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder R, Biswal S (2008) Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 178(6):592–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barnes P (2014) Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med 35(1):71–86

    Article  PubMed  Google Scholar 

  32. Hikichi M, Mizumura K, Maruoka S, Gon Y (2019) Pathogenesis of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke. J Thorac Dis 11(S17):S2129–S2140

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wilschanski M, Rivlin J, Cohen S, Augarten A, Blau H, Aviram M, Bentur L, Springer C, Vila Y, Branski D, Kerem B, Kerem E (1999) Clinical and genetic risk factors for cystic fibrosis-related liver disease. Pediatrics 103(1):52–57

    Article  CAS  PubMed  Google Scholar 

  34. Natarajan V (2020) Is PI3K a villain in cystic fibrosis? Am J Respir Cell Mol Biol 62(5):552–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reilly R, Mroz M, Dempsey E, Wynne K, Keely S, McKone E, Hiebel C, Behl C, Coppinger J (2017) Targeting the PI3K/Akt/mTOR signalling pathway in cystic fibrosis. Sci Rep 7(1):7642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lucas C, Chandra A, Nejentsev S, Condliffe A, Okkenhaug K (2016) PI3Kδ and primary immunodeficiencies. Nat Rev Immunol 16(11):702–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Michalovich D, Nejentsev S (2018) Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol 9:369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Preite S, Gomez-Rodriguez J, Cannons J, Schwartzberg P (2019) T and B-cell signalling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity. Immunol Rev 291(1):154–173

    Article  CAS  PubMed  Google Scholar 

  39. Cabrera-Ortega A, Feinberg D, Liang Y, Rossa C, Graves D (2017) The role of Forkhead box 1 (FOXO1) in the immune system: dendritic cells, T cells, B cells, and hematopoietic stem cells. Crit Rev Immunol 37(1):1–13

    Article  PubMed  PubMed Central  Google Scholar 

  40. Crotty S, Johnston R, Schoenberger S (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 11(2):114–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lederer D, Martinez F (2018) Idiopathic pulmonary fibrosis. N Engl J Med 378(19):1811–1823

    Article  CAS  PubMed  Google Scholar 

  42. Mehrad B, Burdick M, Strieter R (2009) Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol 41(8-9):1708–1718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang X, Xing R, Chen L, Liu C, Miao Z (2016) PI3K/Akt signalling is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis via regulation of epithelial-mesenchymal transition. Mol Med Rep 14(6):5699–5706

    Article  CAS  PubMed  Google Scholar 

  44. Sarris E, Saif M, Syrigos K (2012) The biological role of PI3K pathway in lung cancer. Pharmaceuticals 5(11):1236–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ito K, Caramori G, Adcock I (2006) Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. J Pharmacol Exp Ther 321(1):1–8

    Article  PubMed  CAS  Google Scholar 

  46. Conte E, Fruciano M, Fagone E, Gili E, Caraci F, Iemmolo M, Crimi N, Vancheri C (2011) Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms. PLoS One 6(10):e24663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliott W, Hogg J, Adcock I, Barnes P (2010) Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 182(7):897–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dunn E, Connor J (2012) HijAkt: the PI3K/Akt pathway in virus replication and pathogenesis. Prog Mol Biol Transl Sci 106:223–250

    Google Scholar 

  49. Ji W, Liu H (2008) PI3K-Akt signalling and viral infection. Recent Pat Biotechnol 2(3):218–226

    Article  CAS  PubMed  Google Scholar 

  50. Klann K, Bojkova D, Tascher G, Ciesek S, Münch C, Cinatl J (2020) Growth factor receptor signalling inhibition prevents SARS-CoV-2 replication. Mol Cell 80(1):164–174.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Somanath P (2020) Is targeting Akt a viable option to treat advanced-stage COVID-19 patients? Am J Phys Lung Cell Mol Phys 319(1):L45–L47

    CAS  Google Scholar 

Download references

Author information

Author notes

  1. Biswarup Basu, Sandip Ghosh and Souvik Das contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India

    Biswarup Basu, Sandip Ghosh & Souvik Das

  2. National Institute of Biomedical Genomics, Kalyani, Nadia, West Bengal, India

    Amlan Das

Authors
  1. Biswarup Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandip Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Souvik Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amlan Das
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amlan Das .

Editor information

Editors and Affiliations

  1. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Kamal Dua

  2. Drug Development and Innovation Centre, University of Alberta, Edmonton, AB, Canada

    Raimar Löbenberg

  3. Haematology and Hemotherapy Center, State University of Campinas, Campinas, São Paulo, Brazil

    Ângela Cristina Malheiros Luzo

  4. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Shakti Shukla

  5. School of Pharmaceutical Sciences & Division of Research & Development, Lovely Professional University, Phagwara, Punjab, India

    Saurabh Satija

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Basu, B., Ghosh, S., Das, S., Das, A. (2021). Implications of Phosphoinositide 3-Kinase (PI3K) Signalling in Cellular and Molecular Mechanisms of Respiratory Diseases. In: Dua, K., Löbenberg, R., Malheiros Luzo, Â.C., Shukla, S., Satija, S. (eds) Targeting Cellular Signalling Pathways in Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-33-6827-9_28

Download citation

Publish with us

Policies and ethics

Search

Navigation