Tyrosine kinase report

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  • Our main focus is receptor tyrosine kinases
  • A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases are a subclass of protein kinase.Protein kinases can become mutated, stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Therefore, kinase inhibitors, such as imatinib, are often effective cancer treatments.Most tyrosine kinases have an associated protein tyrosine phosphatase, which removes the phosphate group.
  • Cell surface receptors recruit activity of protein kinases in two general ways: Receptor tyrosine kinases: Possess an intrinsic tyrosine kinase activity that is part of the receptor protein. Examples include receptors for growth factors (PDGF, EGF, insulin, etc.) Non-receptor tyrosine kinases: Receptors lacking self-contained kinase function recruit activities of intracellular protein kinases to the plasma membrane
  • v-src (for viral sarcoma)
  • But how?Event X outside the cell is translated into Event Y inside the cell. Specifically, the signaling molecules (such as hormones) bind the extracellular portion of the receptor protein. This binding event is then somehow communicated to the contents inside the cell. 
  • DOMAINS OF RTK• Extracellular ligand binding domainTransmembrane domain.• Intracellular tyrosine kinase domain, with amino acid sequences in ATP binding and substrate binding regions • Intracellular regulatory domain.Phsphorylated Tyrosine Serve as docking sites for protein with SH2 domains(Src homology region). 
  • 1. Tyrosine kinase receptors are a family of receptors with a similar structure. They each have a tyrosine kinase domain (which phosphorylates proteins on tyrosine residues), a hormone binding domain, and a carboxyl terminal segment with multiple tyrosines for autophosphorylation. When hormone binds to the extracellular domain the receptors aggregate.
  • 2. When the receptors aggregate, the tyrosine kinase domains phosphorylate the C terminal tyrosine residues.
  • 3. This phosphorylation produces binding sites for proteins with SH2 domains. GRB2 is one of these proteins. GRB2, with SOS bound to it, then binds to the receptor complex. This causes the activation of SOS.
  • 4. SOS is a guanyl nucleotide-release protein (GNRP). When this is activated, it causes certain G proteins to release GDP and exchange it for GTP. Ras is one of these proteins. When ras has GTP bound to it, it becomes active.
  • 5. Activated ras then causes the activation of a cellular kinase called raf-1.
  • 6. Raf-1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK.
  • 7. Activated MEK then phosphorylates another protein kinase called MAPK causing its activation. This series of phosphylating activations is called a kinase cascade. It results in amplification of the signal.
  • 8. Among the final targets of the kinase cascade are transcriptions factors (fos and jun showed here). Phosphorylation of these proteins causes them to become active and bind to the DNA, causing changes in gene transcription.
  • Signaling ligands of RTKs: Nerve growth factor (NGF) Platelet-derived growth factor (PDGF) Fibroblast growth factor (FGF) Epidermal growth factor (EGF) insulin and insulin-like GF(IGF-1)ephrins(Eph) vascular endothelial factor(VEGF)
  • EGF results in cellular proliferation, differentiation, and survival.EGF is a low-molecular-weight polypeptide first purified from the mouse submandibular gland, but since then found in many human tissues including submandibular gland, parotid gland. Salivary EGF, which seems also regulated by dietary inorganic iodine, also plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. The biological effects of salivary EGF include healing of oral and gastroesophageal ulcers, inhibition of gastric acid secretion, stimulation of DNA synthesis as well as mucosal protection from intraluminal injurious factors such as gastric acid, bile acids, pepsin, and trypsin and to physical, chemical and bacterial agents.
  • Plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer.Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms.Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDadisulfide-linked transmembrane insulin receptor.
  • Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which, in turn, starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5), and fatty acid synthesis (6)
  • FGThey have been alternately referred to as "pluripotent" growth factors and as "promiscuous" growth factors due to their multiple actions on multiple cell types. Promiscuous refers to the biochemistry and pharmacology concept of how a variety of molecules can bind to and elicit a response from single receptor. In the case of FGF, four receptor subtypes can be activated by more than twenty different FGF ligands. Thus the functions of FGFs in developmental processes include mesoderm induction, antero-posterior patterning, limb development, neural induction and neural development,and in mature tissues/systems angiogenesis, keratinocyte organization, and wound healing processes.Fs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues.
  • (PDGF) is one of the numerous growth factors, or proteins that regulate cell growth and division. It plays a significant role in blood vessel formation (angiogenesis), the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled angiogenesis is a characteristic of cancer. In chemical terms, platelet-derived growth factor is dimeric glycoprotein composed of two A (-AA) or two B (-BB) chains or a combination of the two (-AB).
  • They are important for the growth, maintenance, and survival of neural cells. In addition, NGF has been associated with functional activities of cells of the immune and endocrine systems. NGF appears to act as an inflammatory mediator. It is secreted by various cells in the lungs and by infiltrating inflammatory cells in the bronchial mucosa, playing a possible role in asthma. NGF is also thought to be involved in the development of cardiovascular disease, neuropsychiatric diseases, wound healing, Alzheimer’s disease, and diabetes. NGF and its receptors are also involved in the control of the proliferation and apoptosis of other cell types and therefore of central interest to cancer research.
  • The ephrin-Eph interactions are important in development, especially in cell-cell interactions involved in nervous system patterning (axon guidance) and possibly in cancer. An Eph nomenclature committee adopted a common nomenclature for the receptors and ligands.The Eph name is derived from the cell line from which the first member was isolated, erythropoietin-producing human hepatocellular carcinoma line.Eph receptors have been divided into two groups, designated EphA and EphB, on the basis of sequence homology.
  • VEGF is a sub-family of growth factors, to be specific, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).Serum concentration of VEGF is high in bronchial asthma and low in diabetes mellitus. VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels.When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the retina of the eye and other parts of the body. Drugs such as bevacizumab can inhibit VEGF and control or slow those diseases.

Transcript

  • 1. TYROSINE KINASE by: Mary Jean D. Somcio
  • 2. INTRODUCTION• Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function.
  • 3. HOW SIGNAL IS PASS INSIDE THE CELLL?• Signal Transduction - a basic process involving the conversion of a signal from outside the cell to a functional change within the cell
  • 4. SIGNAL MOLECULES & RECEPTORS • A cell targeted by a particular chemical signal has a receptor protein that recognizes the signal molecule. • When ligands (small molecules that bind specifically to a larger molecule) attach to the receptor protein, the receptor typically undergoes a change in shape.
  • 5. CATEGORIES OF PROTEIN KINASES Classified into three different categories: 1. Kinases that specifically phosphorylate tyrosine residues 2. Kinases that phosphorylate serine and threonine residues, and 3. Kinases with activity toward all three residues.
  • 6. SIGNALING THROUGH ENZYME-LINKED CELL-SURFACE RECEPTORSSix classes:1. Receptor tyrosine kinases2. Tyrosine kinase-associated receptors3. Receptor like tyrosine phosphatases4. Receptor serine/threonine kinases5. Receptor guanylyl cyclases6. Histidine-kinase-associated receptors
  • 7. WHAT IS A TYROSINE KINASE? A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein.
  • 8. FAMILIESApproximately 2000 kinases are known.Among them 90 are tyrosine kinasesThe tyrosine kinases are divided into twomain families: – the trans membrane receptor- linked kinases – those that are cytoplasmic proteins
  • 9. TYPES OF TYROSINE KINASESTyrosine kinases can be furthersubdivided into:1. Receptor tyrosine kinases eg: EGFR, PDGFR, FGFR2. Non-receptor tyrosine kinases eg: SRC, ABL, FAK and Janus kinase
  • 10. RECEPTOR58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies.These are involved in: growth Differentiation Metabolism Adhesion Motility death
  • 11. CYTOPLASMIC/NON-RECEPTOR  32 cytoplasmic protein tyrosine kinases are also known as PTKs.  First non-receptor tyrosine kinase identified was the v-src oncogenic protein
  • 12. RECEPTOR TYROSINE KINASE RTK is like a communication device, since these membrane proteins transmit signals from the cell’s environment into the cell.Tyrosine-kinase receptor is effective when the cell needs to regulate and coordinate a variety of activities and trigger several signal pathways at once.
  • 13. TYROSINE KINASE STRUCTURE Extracellular Domain Transmembrane Domain TK Intracellular Domain
  • 14. MECHANISM OF TYROSINE KINASEProtein/hormone binding with extracellular domain
  • 15. MECHANISM OF TYROSINE KINASE
  • 16. MECHANISM OF TYROSINE KINASE
  • 17. MECHANISM OF TYROSINE KINASE
  • 18. MECHANISM OF TYROSINE KINASE
  • 19. MECHANISM OF TYROSINE KINASE
  • 20. MECHANISM OF TYROSINE KINASE
  • 21. MECHANISM OF TYROSINE KINASE
  • 22. CLASSIFICATION OF RTKsThere are almost 20 classes of RTKs. - EGF receptor - Insuline receptor - FGF receptors - PDGF - VEGF receptor - NGF - ephrins (Eph)
  • 23. EPIDERMAL GROWTH FACTORA growth factor that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR.Human EGF is a 6045-Da protein with 53 amino acid residues and three intramolecular disulfide bonds.
  • 24. INSULINE RECEPTOR (IR)A transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors.
  • 25. INSULINE RECEPTOR (IR)EFFECT OF INSULIN ON GLUCOSE UPTAKE AND METABOLISM Insulin binds to its receptor (1), which, in turn, starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5), and fatty acid synthesis (6)
  • 26. FIBROBLAST GROWTH FACTORFamily of growth factors involved in angiogenesis, wound healing, and embryonic development.The FGFs are heparin-binding proteins and interactions with cell- surface-associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction.
  • 27. PLATELET-DERIVED GROWTH FACTORPotent mitogen for cells of mesenchymal origin, including smooth muscle cells and glial cells.In chemical terms, platelet-derived growth factor is dimeric glycoprotein composed of two A (- AA) or two B (-BB) chains or a combination of the two (-AB).
  • 28. NERVE GROWTH FACTOR A member of a family of small secreted proteins known as neurotropins that function as signaling molecules.
  • 29. EPHRINS (Eph)The Eph family of receptors is the largest known subfamily of receptor tyrosine kinases.The ligands are called ephrins.
  • 30. VASCULAR ENDOTHELIAL FACTORA signal protein produced by cells that stimulates vasculogenesis and angiogenesis.It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.