unit 16: cell signaling Flashcards

1
Q

what are the types of signals received by a cell?

A

Non-chemical signals
- Light (photons)
- Heat, touch

Dissolved gasses
- O2, CO2, NO

Small molecules
- Amino acid and lipid derivatives
- Acetylcholine
- catecholamines (epinephrine, dopamine)
- steroids

Peptides
- Adrenocorticotropic hormone, vasopressin

Proteins
* Protein hormones (e.g. insulin)
* Growth factors (e.g., EGF)
* Cytokines (e.g, interleukins)

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2
Q

types of signaling

A
  • ligands are released/secreted
    • May act either on same cell or cells close-by
    • May act over long distances when released into blood stream
  • ligands remain bound to cell surface
    * Contact-dependent signaling
    * Affects only cells in direct contact
    * Important in immune signaling
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3
Q

how do signaling receptors recognize the signal

A

they are highly specific for signal

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4
Q

what are hydrophobic ligands/signals

A

-steroids
- retinoids
- thyroxine

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5
Q

what receptors do hydrophilic and hydrophobic signals use

A

hydrophilic= transmembrane proteins
small hydrophobic molecules= intracellular receptors

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6
Q

hydrophilic signals

A

small molecules
peptides
proteins

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7
Q

how is the signal relayed

A
  • by intercellular signal transduction proteins and second messengers
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8
Q

what are the signaling outcomes

A
  1. altered protein function (fast),
    - then alters cytoplasmic machinery,
    - leads to changed cell behavior
  2. nucleus (transcription), altered protein synthesis (slow)
    - altered cytoplasmic machinery
    - leads to changed cell behavior
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9
Q

types of short distance intracellular signaling

A
  1. Autocrine signaling
    • target site on the cells that releases the signal
    • many growth factors
  2. paracrine signaling
    - Signaling molecules released affect only target cells in close proximity
    - many growth factors
  3. contact-dependent
    -Signaling molecule remains associated with cell that produced it
    - Cell-cell contact required to transmit the signal
    - Developmental processes, immune responses
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10
Q

types of long distance intracellular signaling

A

Synaptic
* Allows highly directed signaling over long distances by neurons

Endocrine
* Signaling molecules synthesized and secreted into the blood affecting distant cells
* Hormones

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11
Q

binding of signals to their receptors depends on

A

-high specificity of receptors for their ligands
- Binding relies on molecular complementarity and non-covalent interactions
- residues are essential to tight binding with receptor

Kd= [R][L]/[RL]

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12
Q

How is response to cell signals determined

A
  • by Which receptors are expressed on the cell surface
  • the Combination of signals the cell is receiving
  • the Intracellular signaling pathways present in the cell
  • gene expression
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13
Q

what are the cell surface signal transduction pathways

A
  1. receptor-associated kinase
  2. cytosolic kinase
  3. protein subunit dissociation
  4. protein cleavage
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14
Q

Activation of Genes depends on?

A

Gene Accessibility and Presence of Transcription Factors

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15
Q

main types of cell surface receptors

A

Ion-channel- coupled receptors
* Respond to neurotransmitters
* Open or close ion channels in response to ligand binding
- alter the membrane potential and excitability of the target
cell
- Involved in synaptic signaling between nerve cells or nerve and muscle cells

G-protein- coupled receptor (GPCRs)
* Regulate activity of membrane-bound target protein (enzyme or ion channels)
* Seven-transmembrane-domain receptors (7TM)
* Signaling mediated by G-protein
- Ligand binding to receptor activates a membrane- bound G-protein that, in turn, activates a membrane bound effector protein

Enzyme- coupled receptors
* Intrinsic enzyme activity or coupling with enzyme (usually kinase)
* Single-pass membrane proteins
- Ligand binding to the receptor activates an enzyme, often a kinase, that is an endogenous part of the receptor or coupled to the receptor

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16
Q

what are molecular switches

A

– Proteins that are turned on or off by other proteins
– G-proteins (trimeric and monomeric)
– Phosphorylation cascades (Tyr, ser/Thr kinases and phosphatases)

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17
Q

what are second messengers

A

Second messengers
– Low-MW signaling molecules
– Amplify and propagate signal
– Often used to relay signal to distant sites and into organelles – Ca2, cAMP universally used

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18
Q

activated GPCR acts as a what?

A

guanine exchange factor (GEF)

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19
Q

the effector protein acts as a what?

A

GTPase activating protein (GAP) signaling second messengers

20
Q

second messengers in the cytosol are

A

water soluble such as Ca2+, cAMP

21
Q

second messengers in membranes are

A

lipid-soluble second messengers, such as DAG

22
Q
  1. cAMP activates
  2. cGMP
  3. DAG
  4. IP3
A
  1. protein kinase A (PKA)
  2. protein kinase G (PKG) and opens cation channels in rod cells
  3. protein kinase C (PKC)
  4. open ca2+ channels in the ER
23
Q

what are the signaling relay mechanisms

A

Pre-formed signaling complexes
– Grouping of signaling molecules on scaffolds

Induced proximity between signaling molecules
– Receptor activation stimulates transient assemblies of signaling molecules
on cytoplasmic side

Creating phosphoinositide docking sites
– Receptor activation creates a phospholipid modification
– they act as binding sites for signaling molecules

Mediated through interaction domains
– SH2, PTB, etc.

24
Q

describe the interaction domains

A

Src homology 2 (SH2), phosphotyrosine- binding (PTB) domains
- Bind specific phospho- tyr on receptors or intracellular signaling domains

(SH3) domains
- Bind to short pro-rich sequences

Pleckstrin homology (PH) domains
- Bind to charged headgroups of certain phosphoinositides

25
what are the mechanisms of Desensitization to Signals
- Prolonged exposure to stimulus decreases response of the cell 1. separating receptor and signal 2. receptor down regulation 3. receptor inactivation 4. inactivating signal protein 5. producing inhibitory protein
26
examples of GPCR
epinephrine receptor glucagon receptor
27
describe trimetric g-protein
Heterotrimers(α,β,γsubunits) - α, γ subunit membrane-anchored through covalently bound fatty acids - GTP-binding site in α subunit - β, γ subunits associated
28
describe Activation of Trimeric G-Proteins through GPCR
- Ligand binding activates receptor - Active receptor interacts with α subunit - Opens nucleotide binding site of α subunit – Exchange of GDP with GTP (GEF activity of receptor) - GDP/GTP exchange triggers conformational change and dissociation of α subunit from Gβγ -Interaction of activated subunits with effector protein leading to downstream signaling
29
production of cAMP
- produced by activated adenylyl cyclase from ATP - cAMP activates protein kinase A, cAMP dependent kinase causing a downstream effect - hydrolysed by phosphodiesterase (PDE) to AMP
30
GTP-Gas vs GTP-Gai
GTP-Gas stimulates adenylyl cyclase GTP-Gai inhibits adenylyl cyclase
31
how does PKA alter gene expression
- activated PKA phosphorylates transcription factor CREB - Phosporylated-CREB recruits co-factor CBP/P300 - Binds to CRE element (cAMP response element) in DNA, activating transcription
32
what proteins do the Ca-calmodulin complex active
- Myosin light chain kinase (muscle cells) - cAMP phosphodiesterase (PDE) - Protein kinases and phosphatases that regulate the activity of transcription factors
33
what are the controls of the IP3/DAG pathway
- Low cytoplasmic Ca2+ level restored by Calcium pumps in ER and plasma membrane - Phosphatase dephosphorylates IP3 to inositol-1,4-bisphosphate – Cannot bind Ca2+ or IP3-gated channels - Feedback inhibition by reduction of sensitivity of IP3-gated channel to Ca2+ at high Ca2+ levels - Channels close and cytoplasmic Ca2+ levels drop
34
what is the regulation of glycogenolysis by Ca2+ and cAMP/PKA
in muscle cells: - neural stimulation - Ca2+ activates GPK, increases glycogen degradation - hormonal stimulation - cAMP/PKA, decreases glycogen synthesis in liver cells: - hormonal stimulation - DAG/ cAMP activate PKC, decreased glycogen synthesis - IP3/cAMP, increased glycogen degradation
35
describe downregulation for GPCR signaling
- Ligand dissociates - Receptor affinity for ligand reduced after binding of Gas - Binding to effector proteins (e.g., adenylyl cyclase) stimulates GTPase activity of G-protein inhibitor - cAMP phosphodiesterase (PDE) activity reduces cAMP levels by hydrolyzing cAMP to AMP – Reduces activity of PKA Receptor inactivation by phosphorylation – Feedback regulation by phosphorylation of cytoplasmic loops by PKA – Phosphorylation of receptor (ser/thr) sites by GPCR kinases creates sites for inhibitory protein
36
Regulation of Ion Channels by GPCR
- neurotransmitter binds receptor - Gβγ subunit of activated G-protein inhibitor binds to and opens K+ channel
37
clinical correlation of GPCR
- drugs target GPCR
38
enzyme coupled cell surface receptors? examples
Signal through intrinsic enzyme or closely associated enzyme – Phosphorylation of tyrosine or serine/threonine) Receptor tyrosine kinases (RTKs) – Signal through various downstream signaling cascades Cytokine receptors – signal through JAK-STAT pathway TGFβ family receptors – signal through Smads
39
describe Receptor Tyrosine Kinases
- Most abundant enzyme-coupled receptors - Responds to different types of ligands – Growth factors (EGF, insulin, PDGF, FGF), hormones – Both membrane-bound and soluble ligands - Single-pass transmembrane domain - Ligand binding induces dimerization and activation of intrinsic tyrosine kinase activity - Control by receptor endocytosis - Binding of EGF forces out a loop region that engages in dimerization
40
clinical correlation of HER2 (Erb-B2)
HER2 gene amplification and HER2 overexpression in about 25% of breast tumors - Correlates with poor prognosis
41
describe Ras
- Small monomeric G-proteins - Anchored in cell membrane by covalently attached lipid - Activated indirectly through adaptor proteins downstream of receptors - Adapter protein GRB2 binds to activated RTK through SH2 domain - SH3 domain of GRB2 recruits Sos - Sos binds to and activates Ras - Hyperactivated Ras associated with 30% of human tumors
42
describe sos
- acts as GEF for Ras - sos promotes dissociation of GDP from Ras; GTP binds and active Ras dissociates from sos for signaling
43
Ras-Raf-MEK-MAPK Pathway
- Ras is activated and binds Raf then activates it - GTP hydrolysis leads to dissociation of Ras from Raf - Raf activates MEK (phosphorylation) - MEK activates MAPK (phosphorylation) - active MAPk translocates to nucleus and activates transcription factors - expression of proteins necessary for cell proliferation (Early Response genes)
44
describe RTK Signaling through Phospatidylinositols
Activated RTKs can activate an isoform of Phospholipase C (PLC-γ) – Signals through downstream messengers IP3 and DAG Activated RTKs can recruit phosphoinositide-3 kinase (PI-3 kinase) to the plasma membrane – Activates pathways promoting cell survival and proliferation or changes in metabolism
45
explain RTK Activation of Protein Kinase B (PKB) via PI-3 Kinase
- PI-3 kinase is recruited to the plasma membrane by binding of its SH2 domain to the activated RTK. - PI-3K catalyzes the formation of PI-3 phosphates on the cytoplasmic face of the plasma membrane. -PI-3 phosphates serve as docking sites for signaling molecules with PH domain. - PTEN phosphatase inactivates the signaling pathways by hydrolyzing the 3- phosphate in PI 3-phosphates. -PKB activates a factor that inhibits apoptosis, thereby promoting cell survival