• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Signal Transduction Revised
 

Signal Transduction Revised

on

  • 4,603 views

 

Statistics

Views

Total Views
4,603
Views on SlideShare
4,554
Embed Views
49

Actions

Likes
5
Downloads
326
Comments
2

2 Embeds 49

http://mrslil.wikispaces.com 40
http://www.slideshare.net 9

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel

12 of 2 previous next

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Signal Transduction Revised Signal Transduction Revised Presentation Transcript

    • SIGNAL TRANSDUCTION Marigold D.R. Majarucon-Ferrolino, M.D.
    • SIGNAL TRANSDUCTION
      • The process of converting extracellular signals into cellular responses.
      • extracellular signaling molecules ( ligands ) - substances synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules.
    • SIGNAL TRANSDUCTION
    • SIGNAL TRANSDUCTION
      • Receptor – a specific protein that specifically binds a signaling molecule to initiate a response in a target cell
      • Cell responses :
      • changes in gene expression cell morphology
      • cell movements
    • SIGNAL TRANSDUCTION
      • Communication by extracellular signals usually involves six steps:
      • synthesis and
      • 2) release of the signaling molecule by the signaling cell
      • 3) transport of the signal to the target cell
      • 4) detection of the signal by a specific receptor protein
      • 5) a change in cellular metabolism, function, or development triggered by the receptor-signal complex ;and
      • 6) removal of the signal, which often terminates the cellular response.
    • TWO GENERAL KINDS OF CELL RECEPTORS
      • CELL SURFACE RECEPTORS
      • LIGAND – hydrophilic signaling molecules
      • INTRACELLULAR RECEPTORS
      • LIGAND – hydrophobic signaling molecules
    •  
    • CHARACTERISTICS OF RECEPTOR PROTEINS
      • LIGAND-BINDING SPECIFICITY
      • -a ligand binds to a specific receptor
      • EFFECTOR SPECIFICITY
      • receptor-ligand complex mediates a specific cellular response
    • TYPES OF SIGNALING
      • ENDOCRINE SIGNALING - signaling molecules (hormones) act on target cells distant from their site of synthesis by cells of endocrine organs.
      • PARACRINE SIGNALING - the signaling molecules (neurotransmitters) released by a cell only affect target cells in close proximity to it.
      • AUTOCRINE SIGNALING - cells respond to substances (growth factors) which they themselves release.
    •  
    • CLASSIFICATION OF HORMONES BASED ON SOLUBILITY AND RECEPTOR LOCATION
      • SMALL LIPOPHILIC MOLECULES that diffuse across the plasma membrane and interact with intracellular receptors.
      • Examples: steroids, thyroxine and retinoic acid
      • WATER-SOLUBLE HORMONES with cell-surface receptors
      • Examples: Peptide hormones (insulin, growth factors, glucagons)
    • CLASSIFICATION OF HORMONES
      • -SMALL CHARGED MOLECULES ( epinephrine, histamine)
      • LIPOPHILIC HORMONES with cell surface receptors
      • Examples: Prostaglandins
      • ( prostacyclins, thromboxanes,
      • leukotrienes )
    • MAJOR CLASSES OF CELL SURFACE RECEPTORS
      • 1)      G-protein coupled receptors
      • Examples: epinephrine,serotonin, glucagon receptors
      • 2)      Ion channel receptors
      • Example : Acetylcholine receptor
      • 3)      Tyrosine kinase-linked receptors
      • Examples: receptors for cytokines, interferons, and growth factors
      • 4)   Receptors with intrinsic enzymatic activity
      • Examples: receptors for insulin and growth factors
    •  
    • SECOND MESSENGERS
      • - Intracellular signaling molecules
      • 3’ ,5’ cyclic AMP (cAMP)
      • 3’,5’ cyclic GMP (cGMP)
      • 1,2 diacylglycerol (DAG)
      • inositol 1,4,5 triphosphate (IP3) inositol phospholipids (phosphoinositides)
      • Ca++.
    • OTHER INTRACELLULAR SIGNALING PROTEINS IN SIGNAL TRANSDUCTION
      • 1) GTPase Switch Proteins – GTP-binding proteins that act as molecular switches in signal transduction pathways
      • “ ON” when bound to GTP
      • “ OFF” when bound to GDP.
      • Two classes of GTPase switch proteins:
      • a)      Trimeric G protein – coupled directly to activated receptors
      • b)      Monomeric Ras and Ras-like proteins – linked indirectly via other proteins
    • INTRACELLULAR SIGNALING PROTEINS
      • 2) PROTEIN KINASES – carry out the process of phosphorylation
      • -opposed by the activity of protein phosphatases
      • 3) ADAPTER PROTEINS – no catalytic activity
      • - contain domains as docking sites for other proteins
    • MAJOR INTRACELLULAR SIGNALING MECHANISMS
    • SIGNALING VIA G-PROTEIN-COUPLED RECEPTORS (GPCR)
      • G-Proteins – GTP-binding proteins
      • Trimeric proteins ( α β γ )
      • Coupled directly to activated receptors
      • GTPases – convert GTP to GDP + Pi
      • ACTIVE- when GTP is bound
      • INACTIVE – when GDP is bound
    • G-PROTEIN –COUPLED RECEPTOR
    •  
    •  
    • G-PROTEIN-COUPLED RECEPTORS
      • Activate events altering concentrations of intracellular mediators (SECOND MESSENGERS)
      • Common second messengers:
      • cyclic AMP (cAMP)
      • Ca++
    • MAJOR PATHWAYS TO GENERATE SECOND MESSENGERS
    • CYCLIC AMP (cAMP)
      • Second messenger produced from hydrolysis of pyrophosphate from ATP
      • Synthesized by Adenylyl Cyclase
      • Degraded by cAMP phosphodiesterase to form 5’AMP.
    •  
    • CARBOHYDRATE METABOLSIM REGULATION BY cAMP
      • cAMP activates glycogen phosphorylase (glygenolysis)
      • cAMP inhibits glycogen synthase (Glycogenesis)
      • Insulin inhibits cAMP
      • Glucagon and Epinephrine activates cAMP
    • PHOSPHOINOSITIDES
      • Second messengers derived from phosphorylation of inositol by PI kinase
      • Phosphatidyl inositol (PI)
      • PI 4-phosphate (PIP)
      • PI 4,5-Biphosphate (PIP2)
      • Inositol 1,4,5-triphosphate (PI3)
    • TWO BRANCHES OF INOSITOL PHOSPHOLIPID PATHWAY
      • Activated Phospholipase C- ß cleaves PIP2 to generate IP3 and DAG(diacylglycerol)
      • IP3 releases Ca++ from ER
      • DAG together with bound Ca++ activates C-Kinase
      • C-Kinase phosphorylates cell proteins
    •  
    •  
    • SIGNALING BY RECEPTOR TYROSINE KINASES AND RAS
      • LIGANDS- soluble or membrane-bound protein hormones
      • NGF, PDGF, FGF,EGF, insulin
      • Binding stimulates the receptor’s intrinsic protein kinase activity
      • Functions:cell proliferation,differentia-
      • tion,cell survival and metabolism
    • RECEPTOR TYROSINE KINASE (RTK)
      • RAS – the GTPase monomeric protein that transduce signals from RTK
      • ACTIVE – when bound to GTP
      • INACTIVE – when bound to GDP
      • Not directly linked to RTK
    • KEY LINKS OF RAS TO RTK
      • GRB2 – adapter protein for receptor
      • SH2 domain- binds to phosphotyrosine residue in activated receptor
      • SH3 domains- bind to and activate Sos
      • Sos – functions as GEF(guanine nucleotide exchange protein)
      • - converts GDP-Ras to GTP-Ras
    • CYCLING OF RAS BETWEEN ACTIVE AND INACTIVE FORMS
      • Guanine Nucleotide Exchange Factor (GEF) facilitates dissociation of Ras from GDP
      • GTP binds while GEF dissociates yielding active Ras*GTP
      • Hydrolysis of bound GTP to regenerate inactive Ras*GDP.
    •  
    • ACTIVATION OF RAS FOLLOWING BINDING OF LIGAND TO RTK
      • Binding of ligand causes dimerization and autophosphorylation of tyrosine residues
      • Binding GRB2 and Sos couples receptor to inactive Ras
      • Sos promotes dissociation of GDP from Ras
      • GTP binds and Sos dissociates from active Ras
    •  
    • SIGNALING BY MAP KINASE PATHWAY
      • MAP KINASE – serine/threonine kinase
      • Translocates into nucleus to phosphorylate proteins involved in transcription
      • Induced by activated Ras
      • Other proteins involved:
      • Raf – serine/threonine kinase
      • MEK- a dual-specificity protein kinase
    • CASCADE OF PROTEIN KINASES
      • Activated Ras binds to N-terminal of Raf
      • Raf binds to and phosphorylates MEK
      • MEK phosphorylates and activates MAP kinase
      • MAP kinase phosphorylates nuclear transcription factors mediating cellular responses
    •  
    • SIGNALING FROM PLASMA MEMBRANE TO NUCLEUS
      • CRE ( cAmp-response element) – cis-acting DNA sequence in genes regulated by cAMP
      • CREB (CRE-binding protein)- a transcription factor to which CRE binds
      • CBP/300 – a co-activator allowing CREB to stimulate transcription
    • CREB links cAMP to Transcription
      • cAMP activates cAmp-dependent protein kinase (cAPK)
      • cAPK translocates to nucleus and phosphorylates CREB
      • CREB interacts with CBP/300
      • CREB-CBP/300 complex binds to and activates transcription of target genes
    •  
    • MAP KINASES REGULATE TRANSCRIPTION
      • MAP kinase is activated via RTK-Ras pathway
      • translocates to the nucleus and phosphorylates activators and repressors of transcription
    • NF-kß TRANSCRIPTION FACTOR
      • A heterodimer
      • In resting cells, found in cytoplasm
      • bound to an inhibitor I- kß
      • In response to extracellular signal, I- kß is phosphorylated and degraded
      • NF- kß translocates to nucleus and binds to DNA and regulates transcription
    •  
    • THANK YOU!