SUBJECT

Signal Transduction, Immune Receptors

lecture

master

Faculty of Science

Biology MSc

2

Semesters 1-4

Autumn/Spring semester

1. What is signal transduction? Basic molecules and mechanisms of signaling. Intercellular communication, receptors, ligands, molecular recognition, autokrin and parakrin signaling. Four classes of ligand-triggered cell-surface receptors.

2. G protein coupled and enzyme linked signal transduction. Overview of common signaling pathways downstream from G protein – coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). The trimeric G proteins. The structure of G protein linked receptors. Activation of adenylate cyclase and PLCβ. The activation of cAMP dependent protein kinase and the calcium/calmodulin dependent protein kinases. Regulation of G protein linked signaling. Activation of the small G protein, ras.

3. Structural moduls of tyrosine kinases, phosphatases and adaptor proteins. Structure and function of SH2, SH3, PTB, PH, WW and BH domains. The role of tyrosine phosphorylation - functional consequences. Activation of tyrosine kinases and tyrosine phosphatases.

4. The ras/MAP kinase pathway. The mitogen activated protein kinase cascade. Activation of ras. Mitogen activated protein kinases kinase kinase (MAPKKK), MAPKK and MAPK. Extracellular signal regulated kinases, Jun terminal kinase and p38 kinase. Regulation of serine /threonine phosphorylation. Fate determination of signals transmitted by the MAPK cascade

5. Signaling mediated by phosphatidylinositol phosphates. Phosphoinositid metabolism mediated by phosphatidyl inositol 3- Kinase (PI3-K), phosphatidylinositol phosphatases (SHIP and PTEN), and phospholipases (PLC). Models for PI3-K activation. The role of the Gab adaptor proteins. Signals mediated by PI3-K dependent protein kinase (PDK), and PKB/Akt.

6. The function of protein- and inositol phosphatases. Cell membrane and cytosolic tyrosine phosphatases, serine/threonine phosphatases, double scecific phosphatases, inositol phosphatases. Regulation of phosphatase activity.

7. Structure and function of the antigen receptor complex on B cells, B cell signaling. The B cell receptor complex, pre-BCR and BCR. Localization of BCR in lipid rafts. Initiation of membrane proximal signals. Activation of tyrosine kinases. Immunreceptor tyrosine based activation (ITAM). Linker proteins and adapter/scaffolding proteins in B cells. Regulation of the protein kinase C/NFkB pathway.

8. Structure and function of the T cell receptor complex, signal transduction in T cells. Pre-TCR and TCR. The immunological synapse. Clustering of TCR and co-receptors. Membrane proximal signaling in T cells, phosphorylation of ITAMs. Adaptor/scaffolding proteins and co-stimulator molecules in T cells. The CD28, Cbl and CTLA4 mediated pathway.

9. Regulation of B and T cell activation. Co-receptors, with positive and negative regulatory role. Immunreceptor tyrosine based activation (ITAM) and immunoreceptor tyrosine based inhibitory motifs (ITIM)

10. Signaling via Fc receptors. Expression, structure and function of Fc receptors. Binding sites and affinity. Activating and inhibitory Fcg receptors. The mechanism of signal inhibition by ITIM bearing receptors. Signaling via the high affinity Fcg receptors.

11. Activating inhibitory and co-stimulatory NK receptors. Association of NKG2D with intracellular signaling molecules. The signal network that controls cytotoxic function. Models of KIR inhibitory function. Inhibitory NK receptors on T cells.

12. Cytokine receptors: structure and function. Cytokine receptor families. Signaling mediated by ser/thr kinase, IRAK, and by the Janus kinases (JAK). Signaling via the G protein linked chemokine receptors. The regulation of JAK/STAT phosphorylation/activation. Suppressors of cytokine signaling.

13. Signaling mediated by complement receptors and adhesion molecules. Complement receptor families, their structure and function. Signaling via CR2, the positive co-receptors in B cells. Integrins, activation and clustering during leukocyte migration.

14. Toll-like receptors and signaling. The function of TIR domain. The MYD88 adapter family. Ligand specificities of TLR. Toll signaling pathways. Negative regulation of TLR signaling.

• Molecular Biology of the Cell, B. Alberts, M. Johnson et al., Taylor & Francis, 2014;

• B.D Gomperts, I.M. Kramer, P.R. Tatham: Signal transduction, 2nd ed., Academic Press, 2009

• Selected reviews from Current Opinion in Immunology and Nature Reviews in Immunology