Weekly outline
General
All the notes, references, and assignments will be uploaded on to goolge classroom
20 February - 26 February
Toll-Like Receptors (TLRs) play a critical role in the early innate immune response to invading pathogens by sensing microorganism and are involved in sensing endogenous danger signals. TLRs are evolutionarily conserved receptors are homologues of the Drosophila Toll protein, discovered to be important for defense against microbial infection. TLRs recognize highly conserved structural motifs known as pathogen-associated microbial patterns (PAMPs), which are exclusively expressed by microbial pathogens, or danger- associated molecular patterns (DAMPs) that are endogenous molecules released from necrotic or dying cells.27 February - 5 March
The conversion of signal from outside the cell to a functional change within the cell is known as signal transduction. It involves ordered sequences of reactions within the cell, carried out by enzymes, activated by second messengers resulting in an a signal transduction pathway. This pathway has many steps through which the final specific task expected by the cell is achieved. They are compounds located in the extracellular compartment destined to bind on cell plasma membrane receptors and initiate the transduction pathway. First messengers refer to hormones, neurotransmitters, growth factors and cytokine6 March - 12 March
molecule inside cells that acts to transmit signals from a receptor to a target. The term second messenger was coined upon the discovery of these substances in order to distinguish them from hormones and other molecules that function outside the cell as “first messengers” in the transmission of biological information. Many second messenger molecules are small and therefore diffuse rapidly through the cytoplasm, enabling information to move quickly throughout the cell. As elements of signaling pathways, second messengers can serve to integrate information when multiple independent upstream inputs influence the rates of synthesis and degradation of the second messenger13 March - 19 March
One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K). This lipid and the protein kinase that is activated by it AKT trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression. Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.20 March - 26 March
The level of free calcium within the cytosol regulates a range of cellular processes. Complex homeostatic mechanisms based on calcium pumps ensure that the resting level of calcium is kept low (~100 nM). A variety of external signals can trigger an increase in calcium either by promoting an influx of external calcium or by mobilizing calcium from intracellular reservoirs. The ability of many agonists (neurotransmitters, hormones, and growth factors) to generate such calcium signals is very dependent on the hydrolysis of inositol lipids (Michell 1975; Berridge and Fain 1979). This calcium-signaling pathway has a series of transduction steps. The external signal arriving at the cell surface triggers lipid hydrolysis to give inositol trisphosphate, and that then mobilizes the calcium responsible for stimulating a variety of effector systems.27 March - 2 April
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation, adipogenesis, sexually dimorphic growth and other processes. Predictably, mutations that reduce JAK/STAT pathway activity affect these processes (reviewed by Igaz et al., 2001; O'Shea et al., 2002). Conversely, mutations that constitutively activate or fail to regulate JAK signaling properly cause inflammatory disease, erythrocytosis, gigantism and an array of leukemias. Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.3 April - 9 April
Notch signaling has been classically described as direct- ing equivalent cells (or “equivalence groups”), each express- ing both ligand and receptor, to acquire the proper cell fates during development. Detailed studies of this type of “lateral signaling” have implicated Notch in inhibition of “default” primary cell fates, thus allowing expression of secondary fate pathways (reviewed in Beatus and Lendahl, 1998; Greenwald and Rubin, 1992; Kopan and Turner, 1996; Lewis, 1998; Muskavitch, 1994; Rooke and Xu, 1998; Sawamoto and Okano, 1996; Schlosser and Northcutt, 2000; Simpson, 1990; Tiedemann et al., 1998). Notch also participates in multiple developmental processes as a source of “inductive signaling” between nonequivalent cells. In these cases the “signaling” cells (ligand-expressing) and neighboring “receiving” cells (receptor-expressing) are clearly demarcated. Maintenance of germline proliferation in C. elegans, and boundary formation at the dorsal/ventral wing margin of Drosophila are two well-described examples of this type of signaling paradigm10 April - 16 April
Hedgehog, BMP/TGFß, FGF, WNT and Notch signaling pathways constitute the stem cell signaling network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcino- genesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog signaling activation leads to GLI-dependent trans- criptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection.17 April - 23 April
All cells in a multicellular organism are constantly exposed to a variety of extracellular signals that they need to interpret and translate into an appropriate response to their environment. These signals can be soluble factors generated locally (for example, synaptic transmission) or distantly (for example, hormones and growth factors), ligands on the surface of other cells, or the extracellular matrix itself. To achieve this, cells maintain a diversity of receptors on their surface that respond specifically to individual stimuli. These receptors fall into families, based primarily on the way in which they generate the intracellular signals that give rise to the particular functional responses. Moreover, the activity of a given receptor can be modulated by other signalling pathways in a variety of ways, generating the flexibility required of such a complex system. This review aims to describe the function of the major classes of receptor, including G protein coupled receptors, receptor tyrosine kinases, ligand gated ion channels, integrins, and cytokine receptors, and to demonstrate the “crosstalk” that exists between these systems.24 April - 30 April
he conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors, which triggers displacement of the multifunctional kinase GSK-3β from a regulatory APC/ Axin/GSK-3β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, is targeted by coordinated phosphorylation by CK1 and the APC/Axin/GSK-3β-complex leading to its ubiquitination and proteasomal degradation through the β-TrCP/SKP pathway. In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled. This leads to activation of Dishevelled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3β from APC/Axin through an unclear mechanism that may involve substrate trapping and/ or endosome sequestration. The transcriptional effects of Wnt ligand is mediated via Rac1-dependent nuclear translocation of β-catenin and the subsequent recruitment of LEF/ TCF DNA-binding factors as co-activators for transcription, acting partly by displacing Groucho-HDAC co-repressors. Additionally, β-catenin has also been shown to cooperate with the homeodomain factor Prop1 in context-dependent activation as well as repression complexes. Importantly, researchers have found β-catenin point mutations in human tumors that prevent GSK-3β phosphorylation and thus lead to its aberrant accumulation. E-cadherin, APC, and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Furthermore, GSK-3β is involved in glycogen metabolism and other signaling pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders. - See more at: http://www.cellsignal.com/common/content/content.jsp?id=pathways-wnt#sthash.fnSfLG9j.dpuf1 May - 7 May
Mitogen-activated protein kinase (MAPK) modules containing three sequentially activated protein kinases are key components of a series of vital signal transduction pathways that regulate processes such as cell proliferation, cell differentiation, and cell death in eukaryotes from yeast to humans8 May - 14 May
Extracellular matrices (ECM) are secreted molecules that constitute the cell microenvironment, composed of a dynamic and complex array of glycoproteins, collagens, glycosaminoglycans and proteoglycans. ECM provides the bulk, shape and strength of many tissues in vivo, such as basement membrane, bone and cartilage. In vitro, most animal cells can only grow when they are attached to surfaces through ECM. ECM is also the substrate for cell migration. However, ECM provides much more than just mechanical and structural support, with implications in developmental patterning, stem cell niches and cancer. ECM imparts spatial context for signalling events by various cell surface growth factor receptors and adhesion molecules such as integrins. The external physical properties of ECM may also have a role in the signalling process. ECM molecules can be flexible and extendable, and mechanical tension can expose cryptic sites, which could further interact with growth factors or their receptors. ECM proteins and structures can determine the cell behaviour, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors which cooperate in signalling events, determining the signalling outcomes, and thus the cell fate.15 May - 21 May
The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.22 May - 28 May
In multicellular organisms, cells that are no longer needed or are a threat to the organism are destroyed by a tightly regulated cell suicide process known as programmed cell death, or apoptosis. Apoptosis is mediated by proteolytic enzymes called caspases, which trigger cell death by cleaving specific proteins in the cytoplasm and nucleus. Caspases exist in all cells as inactive precursors, or procaspases, which are usually activated by cleavage by other caspases, producing a proteolytic caspase cascade. The activation process is initiated by either extracellular or intracellular death signals, which cause intracellular adaptor molecules to aggregate and activate procaspases. Caspase activation is regulated by members of the Bcl-2 and IAP protein families.29 May - 4 June
Heterotrimeric G proteins have a crucial role as molecular switches in signal transduction pathways mediated by G-protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP–GDP exchange on the G protein α-subunit. The complex series of interactions and conformational changes that connect agonist binding to G protein activation raise various interesting questions about the structure, biomechanics, kinetics and specificity of signal transduction across the plasma membrane.