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Biochem & Cell bio > unit 16: cell signaling > Flashcards

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
Q

what are the mechanisms of Desensitization to Signals

A
  • 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
Q

examples of GPCR

A

epinephrine receptor
glucagon receptor

27
Q

describe trimetric g-protein

A

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
Q

describe Activation of Trimeric G-Proteins through GPCR

A
  • 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
Q

production of cAMP

A
  • 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
Q

GTP-Gas vs GTP-Gai

A

GTP-Gas stimulates adenylyl cyclase
GTP-Gai inhibits adenylyl cyclase

31
Q

how does PKA alter gene expression

A
  • 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
Q

what proteins do the Ca-calmodulin complex active

A
  • Myosin light chain kinase (muscle cells)
  • cAMP phosphodiesterase (PDE)
  • Protein kinases and phosphatases that regulate the activity of transcription factors
33
Q

what are the controls of the IP3/DAG pathway

A
  • 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
Q

what is the regulation of glycogenolysis by Ca2+ and cAMP/PKA

A

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
Q

describe downregulation for GPCR signaling

A
  • 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
Q

Regulation of Ion Channels by GPCR

A
  • neurotransmitter binds receptor
  • Gβγ subunit of activated G-protein inhibitor binds to and opens K+ channel
37
Q

clinical correlation of GPCR

A
  • drugs target GPCR
38
Q

enzyme coupled cell surface receptors? examples

A

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
Q

describe Receptor Tyrosine Kinases

A
  • 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
Q

clinical correlation of HER2 (Erb-B2)

A

HER2 gene amplification and HER2 overexpression in about 25% of breast tumors
- Correlates with poor prognosis

41
Q

describe Ras

A
  • 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
Q

describe sos

A
  • acts as GEF for Ras
  • sos promotes dissociation of GDP from Ras; GTP binds and active Ras dissociates from sos for signaling
43
Q

Ras-Raf-MEK-MAPK Pathway

A
  • 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
Q

describe RTK Signaling through Phospatidylinositols

A

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
Q

explain RTK Activation of Protein Kinase B (PKB) via PI-3 Kinase

A
  • 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

Biochem & Cell bio (20 decks)

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