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Pathways of intracellular signal transduction
- 1. Cell Signalling Presented by Md.Eram Hosen Dept. of Genetic Engineering & Biotechnology University of Rajshahi
- 2. Introduction 1.Receptors Link to other Enzymatic Activity. 2.Pathway of Intracellular Signal Transduction. 3.The Cyclic AMP pathway 4.Cyclic GMP pathway 5.Phospholipids and Ca2+ 6.The PI3-Kinase /Akt and mTOR pathways. 7.MAP Kinase Pathway.
- 3. Receptors Linked to Other Enzymatic Activities Some receptors are associated with other enzymatic activities. These receptors include: • Protein-tyrosine phosphatases, • Protein-serine/threonine kinases, and • Guanylyl cyclases. 1.Protein Tyrosine Phosphatase Function: Removes phosphate groups from phosphotyrosine residues Counterbalance the effects of protein-tyrosine kinases. Negative Role: By terminating the signals initiated by protein-tyrosine phosphorylation. Positive Role: CD45, which is expressed on the surface of T and B lymphocytes. Following antigen stimulation, CD45 is thought to dephosphorylate a specific phosphotyrosine that inhibits the enzymatic activity of Src family members.
- 5. 3.Guanylyl cyclases Guanylyl cyclases catalyzes the formation of cyclic GMP. The receptor guanylyl cyclases have : • An extracellular ligand-binding domain, • A single transmembrane α helix, and • A cytosolic domain with catalytic activity
- 6. Nitric oxide also acts by stimulating guanylyl cyclase
- 7. • Receptors bind to cytoplasmic proteins For example: The cytokine tumor necrosis factor (TNF) induces cell death. TNF Receptor + (Death signaling molecules + Proteases ) TNF Activation of downstream proteases Degradation of a variety of intracellular proteins and death of the cell.
- 8. Pathways of Intracellular Signal Transduction Intracellular signal transduction is a process in which signals transmits from the cell surface to a variety of intracellular targets by the chain of reaction. • Target transcription factors that function to regulate gene expression • Connect the cell surface to the nucleus. The cAMP Pathway: Second Messengers and Protein Phosphorylation Cyclic AMP is a second messenger in hormonal signaling. ATP adenylyl cyclase cAMP cAMP phosphodiesterase AMP
- 9. The effects of cAMP in animal cells are mediated by the action of cAMP-dependent protein kinase or protein kinase A. The inactive form of protein kinase A consists of two regulatory (R) and two catalytic (C) subunits. Binding of cAMP to the regulatory subunits induces a conformational change that leads to dissociation of the catalytic subunits, which are then enzymatically active.
- 10. How does cAMP then signal the breakdown of glycogen? Regulation of glycogen metabolism by protein kinase A Protein kinase A phosphorylates both glycogen synthase and phosphorylase kinase. Glycogen synthase (which catalyzes glycogen synthesis) is inhibited by this phosphorylation, whereas phosphorylase kinase is activated. Phosphorylase kinase then phosphorylates and activates glycogen phosphorylase, which catalyzes the breakdown of glycogen to glucose-1-phosphate.
- 12. cAMP signaling Transduction Pathway Cyclic AMP-inducible gene expression The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein), leading to expression of cAMP- inducible genes.
- 13. Regulation of protein phosphorylation by protein kinase A and protein phosphatase 1
- 14. Role of cGMP in photoreception Cyclic GMP Cyclic GMP is formed from GTP by guanylyl cyclases and degraded to GMP by a phosphodiesterase. Cyclic GMP is responsible for blood vessel dilation, inon channels, sensing smells and photoreception of vertevate eye.
- 15. Phospholipids and Ca2+ phosphatidylinositol 4,5-bisphosphate (PIP2) is a minor component of the plasma membrane, localized to the inner leaflet of the phospholipid bilayer. Diacylglycerol: stimulate distinct downstream signaling pathways protein kinase C. IP3 : stimulate distinct downstream signaling pathways Ca2+ mobilization, so PIP2 hydrolysis triggers a two-armed cascade of intracellular signalin
- 16. Activation of phospholipase C by protein tyrosine kinase Phospholipase C are of two types: Phospholipase C -β - stimulated by G protein Phospholipase C- γ-stimulated by protein tyrosin kinase Activation of phospholipase C by protein-tyrosine kinases Phospholipase C-γ (PLC-γ) binds to activated receptor protein-tyrosine kinases via its SH2 domains. Tyrosine phosphorylation increases PLC-γ activity, stimulating the hydrolysis of PIP
- 17. Ca2 mobilaization by IP3
- 18. Function of calmodulin (Ca2+ binding protein) Calmodulin is a dumbbell shaped protein which has four Ca2+ binding site. Ca2+ and calmodulin together make a complex of Ca2+ /calmodulin, which further activates the inactive target protein kinase. Example- Myosin light chain kinase.
- 19. CaM kinase family CaM kinase family - protein kinases that are activated by Ca2+ /calmodulin. One of the CaM family member is abundant in nervous system which regulate the synthesis and release of neurotransmitters. CaM kinase can also regulate gene expression. Example - CREB(cAMP Response Element Binding protein) which illustrates the similarities between Ca2+ and cAMP signalling pathway.
- 20. Regulation of intracellular Ca2+ in electrically excitable cells
- 21. The PI3 kinase /Akt and mTOR Pathway
- 22. The PI3 (phosphatidylinositol -3 kinase) Kinase / Akt Pathway PIP3 or phosphatidylinositol 3,4,5-trisphosphate (PIP3 ) is produced from PIP2 by the PI3 kinase.
- 23. The PI3 (phosphatidylinositol -3 kinase) Kinase / Akt Pathway Activation of the Akt protein kinase Akt is recruited to the plasma membrane by binding to PIP3 via its pleckstrin homology (PH) domain. It is then activated as a result of phosphorylation by another protein kinase (PDK) that also binds PIP3.
- 24. The regulation of FOXO
- 25. The mTOR pathway
- 26. The MAP Kinase Pathway The MAP kinase or mitogen-activated protein kinases pathway refers to a cascade of protein kinases that are highly conserved in evolution and play central roles in signal transduction in all eukaryotic cells, ranging from yeasts to humans. The MAP kinase are activated in response to a variety of growth factors and other signaling molecules. In yeasts, MAP kinase pathways control a variety of cellular responses, including mating, cell shape, and sporulation. In higher eukaryotes (including C. elegans, Drosophila, frogs, and mammals), MAP kinases are ubiquitous regulators of cell growth and differentiation
- 27. Activation of the ERK MAP Kinases Activation of the ERK MAP kinases Stimulation of growth factor receptors leads to activation of the small GTP-binding protein Ras, which interacts with the Raf protein kinase. Raf phosphorylates and activates MEK, a dual-specificity protein kinase that activates ERK by phosphorylation on both threonine and tyrosine residues (Thr-183 and Tyr-185). ERK then phosphorylates a variety of nuclear and cytoplasmic target proteins.
- 28. Regulation of Ras proteins
- 29. Small GTP-binding proteins The Ras proteins are prototypes of a large family of approximately 50 related proteins, frequently called small GTP-binding proteins. Examples: Rheb protein: Regulate m TOR signaling . Rab proteins : function to regulate vesicle trafficking, Ran protein : involved in nuclear protein import , Rho protein : organization of the cytoskeleton.
- 30. Mode of Ras activation that mediated by receptor protein-tyrosine kinases
- 31. Induction of immediate-early genes by ERK Cyclic AMP-inducible gene expression The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein), leading to expression of cAMP- inducible genes.
- 32. Pathways of MAP kinase activation in mammalian cells
- 33. • Thanks to All
Editor's Notes
- Thus, the CD45 protein-tyrosine phosphatase acts (somewhat paradoxically) to stimulate nonreceptor protein-tyrosine kinases. CD45 (lymphocyte common antigen) is a receptor-linked protein tyrosine phosphatase that is expressed on all leucocytes, and which plays a crucial role in the function of these cells. Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and ...
- Protein-serine/threonine kinases The receptors for transforming growth factor β (TGF-β) and related polypeptides are protein kinases that phosphorylate serine or threonine, rather than tyrosine, TGF-β is the prototype of a family of polypeptide growth factors that control proliferation and differentiation of a variety of cell types, generally inhibiting proliferation of their target cells. Cloning TGF-β family - Found a unique receptor family with a cytosolic protein-serine/threonine kinase . The binding of ligand to these receptors results in the association of two distinct polypeptide chains, which are encoded by different members of the TGF-β receptor family, to form heterodimers in which the receptor kinases cross-phosphorylate one another. The activated TGF-β receptors then phosphorylate members of a family of transcription factors called SMADs, which translocate to the nucleus and stimulate expression of target genes.
- Some receptors has cytosolic domains of guanylyl cyclases, Nitric oxide also acts by stimulating guanylyl cyclase, but the target of nitric oxide is an intracellular enzyme rather than a transmembrane receptor.. Ligand binding stimulates cyclase activity, leading to the formation of cyclic GMP—a second messenger whose intracellular effects are discussed in the next section of this chapter.
- Nitric oxide also acts by stimulating guanylyl cyclase, but the target of nitric oxide is an intracellular enzyme rather than a transmembrane receptor.. Ligand binding stimulates cyclase activity, leading to the formation of cyclic GMP—a second messenger whose intracellular effects are discussed in the next section of this chapter.
- eliminating damaged or unwanted cells from tissues
- eading to changes in gene expression in response to extracellular stimuli 2. the first messenger being the hormone itself) Epinephrine receptor is coupled to adenylyl cyclase via a G protein that stimulates enzymatic activity and increasing the intracellular concentration of cAMP.
- The inactive form of protein kinase A is a tetramer consisting of two catalytic and two regulatory subunits (Figure 13.19). Cyclic AMP binds to the regulatory subunits, leading to their dissociation from the catalytic subunits. The free catalytic subunits are then enzymatically active and able to phosphorylate serine residues on their target proteins
- In the regulation of glycogen metabolism, protein kinase A phosphorylates two key target enzymes (Figure 13.20). The first is another protein kinase, phosphorylase kinase, which is phosphorylated and activated by protein kinase A. Phosphorylase kinase in turn phosphorylates and activates glycogen phosphorylase, which catalyzes the breakdown of glycogen to glucose-1-phosphate. In addition, protein kinase A phosphorylates the enzyme glycogen synthase, which catalyzes glycogen synthesis. In this case, however, phosphorylation inhibits enzymatic activity. Elevation of cAMP and activation of protein kinase A thus blocks further glycogen synthesis at the same time as it stimulates glycogen breakdown.
- How are signals amplified inside cells? A signal may reach a cell in the form of a single hormone molecule. Inside the cell, the signal must be amplified so that the response is carried out multiple times rather than just be a single molecule. Amplification is built into the system. Any molecule that catalyzes a reaction can do so multiple times producing more than one product molecule. So each step in the signaling chain has the potential for amplification. If a signaling chain is several steps long then there is a great potential for amplification of the signal. For example if the membrane receptor can produce 10 second messengers and each second messenger can generate the transcription of 10 mRNA chains then the signal has been amplified one thousand fold.
- increases in cAMP activate the transcription . signal is carried from the cytoplasm to the nucleus by the catalytic subunit of protein kinase A target genes that contain cAMP response elements CRE , protein kinase A phosphorylates a transcription factor called CREB leading to the activation of cAMP-inducible genes. cAMP plays important roles in controlling the proliferation, survival, and differentiation of a wide variety of animal cells.
- The phosphorylation of target proteins by protein kinase A is reversed by the action of protein phosphatase 1.
- Different types of guanylyl cyclases are activated by both nitric oxide and peptide ligands. The best-characterized role of cGMP is in the vertebrate eye, where it serves as the second messenger responsible for converting the visual signals received as light to nerve impulses. The photoreceptor in rod cells of the retina is a G protein-coupled receptor called rhodopsin (Figure 13.23). Rhodopsin is activated as a result of the absorption of light by the associated small molecule 11-cis-retinal, which then isomerizes to all-trans-retinal, inducing a conformational change in the rhodopsin protein. Rhodopsin then activates the G protein transducin, and the α subunit of transducinstimulates the activity of cGMP phosphodiesterase, leading to a decrease in the intracellular level of cGMP. This change in cGMP level in retinal rod cells is translated to a nerve impulse by a direct effect of cGMP on ion channels in the plasma membrane, similar to the action of cAMP in sensing smells.
- Cyclic GMP (cGMP) is also an important second messenger in animal cells, although its roles are not as clearly understood as those of cAMP A variety of hormones and growth factors stimulate the hydrolysis of PIP2 by phospholipase C—a reaction that produces two distinct second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (IP3).