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    Biosignaling Biosignaling Biosignaling Biosignaling

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    AG Khan
    Biosignaling is fundamental to life as cells constantly receive and respond to internal and external signals. Signal transduction involves signal molecules being detected by receptors and converted into a cellular response through a chemical process. There are a few conserved mechanisms that organisms use to detect signals extracellularly and transduce them into intracellular changes. These pathways involve signal molecules binding to receptor proteins which activate intracellular signal molecules and lead to changes in target proteins and cellular responses like changes in gene expression.

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    Biosignaling Biosignaling Biosignaling Biosignaling

    Uploaded by

    AG Khan
    49 views48 pages
    Biosignaling is fundamental to life as cells constantly receive and respond to internal and external signals. Signal transduction involves signal molecules being detected by receptors and converted into a cellular response through a chemical process. There are a few conserved mechanisms that organisms use to detect signals extracellularly and transduce them into intracellular changes. These pathways involve signal molecules binding to receptor proteins which activate intracellular signal molecules and lead to changes in target proteins and cellular responses like changes in gene expression.

    Original Description:

    cell signaling presentation

    Original Title

    Ch12-I

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    Biosignaling is fundamental to life as cells constantly receive and respond to internal and external signals. Signal transduction involves signal molecules being detected by receptors and converted into a cellular response through a chemical process. There are a few conserved mechanisms that organisms use to detect signals extracellularly and transduce them into intracellular changes. These pathways involve signal molecules binding to receptor proteins which activate intracellular signal molecules and lead to changes in target proteins and cellular responses like changes in gene expression.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    49 views48 pages

    Biosignaling Biosignaling Biosignaling Biosignaling

    Uploaded by

    AG Khan
    Biosignaling is fundamental to life as cells constantly receive and respond to internal and external signals. Signal transduction involves signal molecules being detected by receptors and converted into a cellular response through a chemical process. There are a few conserved mechanisms that organisms use to detect signals extracellularly and transduce them into intracellular changes. These pathways involve signal molecules binding to receptor proteins which activate intracellular signal molecules and lead to changes in target proteins and cellular responses like changes in gene expression.

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    Biosignaling

    Biosignaling is fundamental to life


    Cells constantly receive and act on signals from
    the internal and external environments.

    Bacterial cells receive constant input from


    membrane receptors that sample the surrounding
    medium for pH, osmotic strength, the availability
    of food, chemical, oxygen, light, etc.

    Biosignaling is fundamental to life

    Biosignaling is fundamental to life

    Signal transduction
    The process that a signal which represents information is detected by specific receptors and converted
    to a cellular response is called signal transduction
    transduction..
    Signal transduction always involves a chemical
    process.
    Even though the number of different biological signaling is large, organisms use just a few evolutionary
    conserved mechanisms to detect extracellular signals
    and transduce them into intracellular changes.

    Basic signaling pathway


    Signal
    molecule

    Receptor
    protein
    Intracellular
    signal
    molecule

    Target
    proteins
    Cellular
    Response

    Changes of
    gene expression

    If signal transduction goes wrong


    ..
    wrong

    Wild type

    Mutant

    The mutant with abnormal


    gravitropism

    BR-insensitive
    mutant

    If signal transduction goes wrong


    ..
    wrong

    Wild-type

    Mutants

    General features of signal transduction


    Specificity
    Amplification
    Desensitization
    Integration

    Specificity of signal transduction


    Signal transduction is remarkably specific.

    Amplification of signal transduction


    Signal transduction is also exquisitely sensitive
    sensitive.. It is
    because of high affinity of receptors, cooperativity in
    ligand-receptor interaction, and amplification of the
    signal by enzyme cascade.

    Desensitization of signal transduction


    When a signal is present continuously, desensitization
    of the receptor system occurs.

    Integration of signal transduction


    Organisms are able to receive multiple signals and
    produce a unified response appropriate to their needs.

    Multiple signals are needed to maintain cell activity


    Input of signals

    Output of responses

    Synergism and antagonism


    Synergism:
    Two signals act at their targets
    so that the combination is more
    than additive.

    Integrator
    protein

    Pathway cross-talk

    Antagonism:
    Two signals exert opposite
    physiological functions.
    Note:
    These interactions do not have
    to work through the same
    receptor.

    Multiple levels of cell signaling

    Six basic mechanisms for signal transduction

    Receptor tyrosine kinase


    G protein-coupled receptors
    Receptor guanylyl cyclases
    Receptor
    Gated ion channels
    Gated
    Adhesion receptors
    Adhesion
    Nuclear receptors (steroid
    Nuclear
    receptor)

    Receptor enzymes
    The receptor enzymes have a ligand-binding domain
    on the extracellular surface of the plasma membrane
    and an enzyme active site on the cytosolic side, with
    the two domains connected by a single transmembrane
    segment.
    Commonly, the receptor enzyme is a protein kinase
    that phosphrolates Tyr residues in specific target
    proteins. In plants, the protein kinase of receptors is
    specific for Ser or Thr residues.

    Production of insulin

    Pancreas

    Insulin is involved in regulating gene expression


    and glucose metabolism.

    Activation of gene expression by insulin

    Activation of gene expression by insulin

    IRS-1: Insulin receptor substrate-1

    Activation of the insulin-receptor Tyr kinase


    Insulin

    Activation of gene expression by insulin

    IRS-1: Insulin receptor substrate-1

    SH2 and SH3 domains

    Src homology domain 2


    It is a common domain involved in protein-protein
    interactions through the binding to a particular site on
    the target protein
    protein.. The typical binding site is only 3-5
    amino acids long, consisting of a phosphotyrosine and
    the other amino acid on its C-terminal site
    site.. The SH2
    domain is a region of ~100 amino acids
    acids..

    Src homology domain 3


    It is a common domain involved in protein-protein
    interactions through the binding to a proline-rich region on
    the target protein
    Grb2 protein has one SH2 domain and one SH3 domain

    Recognition of phosphotyrosine
    by the SH2 domain
    NH3+
    Amino acid
    position

    Phosphotyrosine

    -1
    0

    Phosphotyrosine
    pocket

    +1
    +2
    +3

    CHCH2CH3
    CH3

    Specificity
    pocket

    SH2 domain
    The interacting
    protein

    COO-

    Side chains of the


    Interacting protein

    Activation of gene expression by insulin


    Sos is also called a GEF protein
    (Guanosine nucleotide-exchange
    factor).

    IRS-1: Insulin receptor substrate-1


    Ras is also called small G protein.

    Structure of Ras ( a small G protein)

    GTP-bound Ras

    Activation of gene expression by insulin

    Activation of gene expression by insulin

    Protein kinase families


    The protein Raf-1, MEK, and ERK are members
    of three families.
    Raf-1

    MAPKKK

    MEK

    MAPKK

    (MAP Kinase kinase,


    specific for Ser and Tyr)

    ERK

    MAPK

    (MAP Kinase,
    specific for Ser and Thr)

    (MAP Kinase kinase kinase,


    specific for Ser or Thr)

    MAPK: Mitogen-activated protein kinase

    Mitogen-activated protein kinase

    In the hunt for tyrosine kinase substrates, a superfamily


    of protein kinases were identified around 1990.

    They were initially demonstrated to phosphorylate


    microtubule-associated protein (MAP); now the acronym
    remains, but with a different meaning: mitogen-activated
    protein kinase.
    (Mitogens: the substances that induce mitosis)

    They are dually phosphorylated by their upstream


    kinases (MAP kinase kinase) on both Ser/Thr and
    Tyr.

    Receptor tyrosine kinase

    Ligand
    binding
    domains

    Kinase
    domains

    Insulin receptor

    Epidermal growth Platelet-derived Fibroblast growth


    growth factor
    factor receptor
    factor receptor
    receptor

    Plant receptor kinases

    LRR-type
    BR signaling

    CR4-like
    Epidermal cell
    differentiation

    Meristem
    organization
    Pathogen defense

    WAK type

    S-domain type Lectin type

    Function
    unknown

    Self-incompatible Fuction
    pollination
    unknown

    Arabidopsis genome has 417


    receptor kinase genes!!!

    Phosphorylation cascades

    ~ 1/3 of the proteins in a cell are phosphorylated at any


    given time
    Moreover, many of the signaling proteins controlled
    by phosphorylation are themselves protein kinases
    These are organized in phosphorylation
    cascades

    One protein kinase , activated by


    phosphorylation, phosphorylates the next
    protein kinase in the sequence, and so on,
    relaying the signal onward

    Activation of glycogen synthase by insulin

    Activation of glycogen synthase by insulin

    PIP2
    PI-3K: Phosphoinositide 3-kinase
    PIP2: Phosphatidylinositol 4,5-bisphosphate
    PIP3: Phosphatidylinositol 3, 4,5-triphosphate
    PKB: Protein kinase B

    Activation of glycogen synthase by insulin

    PKB: Protein kinase B


    GSK3: Glycogen synthase
    kinase 3
    GS: Glycogen synthase

    Activation of glycogen synthase by insulin

    PKB: Protein kinase B


    GLUT4: Glucose transporter 4

    Activation of glycogen synthase by insulin

    To prevent the continuous activation of PI-3K-PKB


    pathway, a PIP3-specific phosphatase (PTEN) is required
    to removethe phosphoryl group at the 3
    3 position of PIP3
    to produce PIP2, which no longer serve as a binding site
    for PKB, and signaling chain is broken.
    When PTEN gene is mutated, the cells will accumulate
    abnormal high level of PIP3 which lead unstopped cell
    division, thus cause tumor growth.

    CB1 is a receptor in plasma membrane of human brain.


    When it got continuously excited, it leads to excessive
    neuronal activity which causes epilepsy. Anandamide is
    a ligand that binds to CB1 receptor to prevent epilepsy.
    THC, the active ingredient of marijuana, can activates CB1
    receptor and stimulates appetite. It has also been used to
    treat epilepsy.
    Many drugs act through the interaction with receptors.

    Receptors with no intrinsic enzyme activity

    JAK (Janus kinase or


    Just another kinase)
    STAT ((S
    Signal transducers and
    activators of transcription)
    NLS: Nuclear localization signal

    Regulation of the formation of erythrocytes


    by erythopoietin (EPO)

    The guanylyl cyclases are receptor enzymes

    ANF regulates renal excretion


    of Na+, causes relaxation of
    the blood vessel.
    Guanylin regulates Cl - secretion in the intestine.
    NO induces relaxation of
    cardiac muscle

    cGMP as second messenger

    Guanylyl
    cyclase

    Most of the action of cGMP in


    animals are believed to be
    mediated by cGMP-dependent
    protein kinase.

    The guanylyl cyclases are receptor enzymes

    The guanylyl cyclases activated by NO

    In the heart, elevated cGMP resulting from


    NO binding reduces the forcefulness of contraction.
    Nitroglycerin can yield a steady stream of
    NO for several hours, causing long lasting
    relaxation of cardiac muscle.

    Some key points we have learned


    All cells have specific and highly sensitive signaltransducing mechanisms, which have been conserved
    during evolution
    All the signaling mechanisms have four characteristics:
    Specificity, affinity, amplification, and desensitizing.
    Eukaryotic cells have six general types of signaling
    mechanisms.
    Insulin receptor is the prototype of receptor enzymes
    with Tyr kinase activity. The binding of insulin to the
    receptor triggers a phosphorylation cascade.

    Some key points we have learned


    Many signaling proteins have domains that bind to
    phosphorylated Tyr, Ser, or Thr resideus in other
    proteins; the binding specificity for each domain is
    determined by sequences that adjoin the phosphorylated residues.
    In the JAK-STAT signaling system, a soluble protein
    Tyr kinase (JAK) is activated by association with a
    receptor, and then phosphorylates the transcription
    factor STAT, which enters the nucleus and alters the
    expression of a set of genes.
    Some signals act through receptor enzymes with
    guanylyl cyclase activity.

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