Cell signalling
- 1. Cell Signaling pathway ▪ Presenter: Dr. Anup Goswami ▪ Moderator: Prof. Th. Nandakishore
- 2. Introduction ▪ Signal transduction derived from “transduce” meaning to lead across ▪ Extracellular signalling molecule activates receptor thus creates a ‘response’ ▪ Various processes coordinates individual cells to support the organism as a whole ▪ Hormones, Growth factors, Cytokines, physiological molecules, drugs ▪ Diseases like diabetes, psoriasis arise from defective pathways remains area of research
- 3. Some Basic Terminologies ▪ Receptor: Protein molecules receives chemical signal from outside the cell, e.g- G- protein coupled receptor, Glucocorticoid receptor ▪ Ligand: Ion / molecules (functional) group binds with the receptor ,serving biological purpose, e.g- hormones, drugs, ions etc ▪ Second messenger: Intra- cellular signaling molecules released by the cells to trigger physiological changes, e.g- c- AMP, c- GMP, IP3, DAG, Calcium
- 6. G- protein- coupled receptors (Receptor proteins)
- 8. G- protein- coupled receptors (Receptor proteins) Psoriasis PDE inh.in AD
- 9. Applied Aspects: When C-AMP pathway is dysregulated-can influence the pathogenesis of inflammatory cutaneous diseases e.g- Psoriasis, Atopic dermatitis In these diseases c-AMP & it’s effector protein (PKA) are downregulated So elevation of c-AMP may be a therapeutic option Apremilast: a selective PDE4 inhibitor, inhibits the pro-inflammatory cytokines e.g- TNF@, IFN y, IL-12, IL-17, IL-23 CRISABOROL: a PDE4 inhibitor Other drugs: - E 6005, -LEO 29102, -Roflumilast, -Isoxazoline derivative ( PDE4/PDE7 inhibitor)
- 10. ▪ PDE4 inhibitors in other Inflammatory skin disease: - Lichen planus - DLE - Cutaneous sarcoidosis Levy J, Zhou DM, Zippin JH (2016) Cyclic Adenosine Monophosphate Signaling in Inflammatory Skin Disease. J Clin Exp Dermatol Res 7: 326. doi:10.4172/2155-9554.1000326
- 11. Model of Receptor tyrosine kinase- an enzyme linked Receptor
- 12. Transmembrane enzyme linked receptor signalling ▪ Insulin acts through this pathway ▪ Growth factors, cytokines, ANF acts through above mentioned pathway ▪ Biological agents: a. Alefacept- a receptor –Ab fusion protein, LFA 3 & Fc IgG 1, bindind site- CD2, in moderate- severe psoriasis b. Efalizumab: Human monoclonal Ab,human IgG1, binding site- CD 11a & LFA 1, in mod- severe psoriasis c. Adalimumab: Human monoclonal Ab, IgG1, binding site- TNF@, used in- psoriasis, severe psoriatic arthritis, RA, AS, CD d. Etanercept: Receptor –Ab fusion protein, binding site TNF@, in Psoriasis, psoriatic arthritis, AS, RA e. Infliximab: chimeric monoclonal Ab, binds to TNF @, in Psoriasis, psoriatic arthritis, RA, AS, UC, CD
- 13. ▪ Etolizumab: a novel anti CD6 monoclonal antibody- in mod- severe chronic plaque psoriasis ▪ IVIg: composed of > 90% IgG, minimal amount of IgA, sol. CD4, CD8, HLA molecules, cytokines
- 14. Receptors regulating gene expression (Transcription factors, nuclear receptor)
- 15. Jak – STAT pathway:
- 16. JAK- STAT pathway ▪ Components- 1. Receptor 2. Ligands- prolactin ,EPO, thrombopoietin,IFN,ILs JAK- Janus Kinase – is an enzyme uses ATP to phosphorylates other proteins 4 types- JK1,JK2,JK3 & Tyrosine kinase 2 STAT: signal transducer + activator of transcription JAK 2 mutation: most important, seen in- a. Chronic myeloproliferative disorder b. Polycythemia Vera c. Essential Thrombocytopenia d. Myelofibrosis Surprisingly not seen in CML In hyper-IgE syndrome: STAT-3 Mutation
- 17. JAK- STAT pathway ▪ Tofacitinib, filgotinib—JAK3 inhibitor—clinical trials ▪ Cytokines play key roles in controlling cell growth and the immune response via cytokine receptors which in turn rely on the JAK enzymes for signal transduction ▪ Hence drugs that inhibit the activity of these Janus kinases block cytokine signalling ▪ Under development for the treatment of psoriasis, vitiligo, rheumatoid arthritis, polycythemia vera, essential thrombocythemia , ulcerative colitis, myeloid metaplasia , myelofibrosis ▪ Roxolitinib- a Janus Kinase inhibitor- tried in sepsis due to Candida albicans
- 18. RAS- Mitogen activated protein kinase signaling pathway:
- 20. Inhibitors of MAP-K pathway: ▪ Sorafenib – a RAF kinase inhibitor. ▪ Other RAF inhibitors: ▪ SB590885 ▪ PLX4720 ▪ XL281 ▪ RAF265 ▪ Encorafenib ▪ Dabrafenib ▪ Vemurafenib ▪ Some MEK inhibitors : ▪ Cobimetinib ▪ CI-1040 ▪ PD035901 ▪ MEK162 ▪ Selumetinib ▪ Trametinib(GSK1120212)
- 21. Wnt/b- Catenin signaling pathway:
- 22. References ▪ Bolognia, 3rd edition ▪ Goodman & Gillman’s The Pharmacological basis of Therapeutics- 12th ed. ▪ Essential of Medical pharmacology, 7th Ed. By K.D. Tripathi ▪ Ganong’s Review of Medical Physiology, 25th Ed.by Kim E. Barrett ▪ Levy J, Zhou DM, Zippin JH (2016) Cyclic Adenosine Monophosphate Signaling in Inflammatory Skin Disease. J Clin Exp Dermatol Res 7: 326. doi:10.4172/2155-9554.1000326 ▪ Internet
- 23. Thank You