Chapter 17: Cell Signaling Flashcards
what are the 4 steps in cell signaling?
- ligand/receptor binding
- activation of signal transduction
- relay of signal to the interior of the cell
- cellular responses/changes in gene expression
what are the 2 modes of cell signaling?
- direct cell-to-cell-signaling
- signaling by secreted molecules
explain direct cell-to-cell signaling
direct interaction of a cell w/ its neighbor or the cell matrix
what type of cell signaling is important in early development?
direct cell-to-cell
what are the 3 types of signaling by secreted molecules?
- endocrine signaling
- paracrine signaling
- autocrine signaling
describe endocrine signaling
- signaling molecules are secreted by specialized endocrine cells & carried through the circulatory system
endocrine signaling acts on target cell at
distant body sites
what is an example of endocrine signaling molecule
hormones
describe paracrine signaling
signaling molecules act locally & affect the behavior of nearby cells
what is an example of a paracrine signaling molecule?
neurons via neurotransmitters
describe autocrine signaling
cells respond to their own signaling molecules
what is an example of an autocrine signaling molecule?
T lymphocytes & cancer cells
what are the 2 types of signaling molecules?
- non-surface receptor-binding ligands
- cell surface receptor ligands
give some examples of non-surface receptor-binding ligands
- steroid hormones
- thyroid hormone
- retinoic acid
- vitamin D3
- nitric oxide
- carbon monoxide
steroid hormones are synthesized from
cholesterol
steroid hormones are VERY
hydrophobic
give 3 examples of steroid hormones
- sex steroids
- mineralocorticoids
- corticosteroids
give 3 examples of sex steroids
- testosterone
- estrogen
- progesterone
what is an example of corticosteroids
glucocorticoids
what is considered to be a very important signaling molecule?
nitric oxide
steroid hormone receptors are typically found on the
inside of the cell
with non-surface receptor-binding ligands, after the intracellular receptors bind to the ligands they
diffuse across the membrane
what are the 4 main examples of cell surface receptor ligands
- neurotransmitters
- peptide hormones
- growth factors
- eicosanoids
give 5 examples of a neurotransmitter
- acetylcholine
- dopamine
- epinephrine
- serotonin
- GABA
give 7 examples of a peptide hormone
- insulin
- glucagon
- prolactin
- oxytocin
- FSH
- growth hormone
- neuropeptides
give 8 examples of GFs
- NGF
- neurotrophins
- BDNF
- EGF
- PDGF
- TGF-B
- FGF
- VEGF
BDNF: brain derived neutrophic factor
eicosanoids are similar to steroids but they
bind to surface receptors
give 2 examples of eicosanoids
- prostaglandins
- leukotrienes
what is the function of leukotrienes
inflammatory response by COX-1 and COX-2
what are the 5 major types of cell surface receptors?
- G protein-coupled receptors (GPCRS)
- ion channel receptors
- receptors w/ intrinsic enzyme activity
- receptor protein tyrosine kinases
- cytokine receptors & nonreceptor protein-tyrosine kinases (NrPTKs)
explain GTP-binding
the binding of a ligand activates a G protein
describe the 3 steps in GPCRs
- GTP-binding
- G protein activates enzyme
- catalyzes the synthesis of a second messenger
what second messengers are generated from the effector enzyme?
- cAMP
- inositol 145-triphosphate (IP3)
- 1,2-diacylglycerol (DAG)
the effector molecule is on the
cytosolic side of the membrane
GPCRs have ____ transmembrane alpha-helices
7
G-protein is a
heterotrimer
to what subunit does GTP bind to on the G-protein?
alpha subunit
why can g-protein activate 2 things at once?
b/c the alpha subunit dissociates from the gamma & beta subunits
how does the G protein become inactive
by hydrolyzing the bound GTP to GDP
after the G-protein hydrolyzes GTP to GDP the subunits
recombine to form the inactive G-protein
the activation of adenylyl cyclase occurs through
binding of a hormone which in turn activates a G-protein
the hormonal activation of adenylyl cyclase occurs through a
GPCR
what are the functions of adenylyl cyclase?
- generates cAMP by cleaving two phosphates off of ATP
how is a ion channel opened?
by ligand binding which triggers a conformational change
what causes the opening of additional ion channels?
membrane depolarization
when ion channels close the ligand is
degraded or recycled
in receptors with intrinsic enzymatic activity the cytosolic domains typically have
catalytic activity
some receptors with intrinsic enzymatic activity are monomers w/
guanylyl cyclase activity
some receptors with intrinsic enzymatic activity form
dimers w/ tyrosine kinase activity
the receptors that form dimers with tyrosine kinase activity form
SH2 binding sites
receptors for many growth factors have
intrinsic protein-tyrosine kinase activity
ligand binding to receptor tyrosine kinases causes the formation of an… and phosphorylation of its
- activated homodimer
- own cytosolic domain & substrate proteins
the receptor for epidermal growth factor (EGF) is typically a
receptor tyrosine kinase
the receptor tyrosine kinase is typically
1 transmembrane segment
what portion of the receptor tyrosine kinase binds the ligand?
the extracellular portion
the receptor tyrosine kinase has a series of _________ residues that are _________ for the _____________ __________.
- tyrosine
- substrates
- tyrosine kinase
binding of second messenger (EGF) to a receptor tyrosine kinase causes receptor
aggregation & clustering
receptor tyrosine kinase ______________ each other at multiple tyrosine residues
cross-phosphorylate
what on the receptor tyrosine kinase creates binding sites for downstream molecules?
tyrosine phosphate residues
formation of phosphotyrosine residues on the receptor creates binding sites for downstream signaling molecules that contain
SH2 domains
SH: Scr homology
what is the ligand for Ca2+ channels in the ER
InsP3
list the 4 steps in NrPTKs
- ligand binding forms homo/heterodimer
- triggers activation of cytosolic protein-tyrosine kinase
- activated kinase phosphorylates tyrosine in receptor
- substrate proteins bind phospho-tyrosine residues & become phosphorylated
the cytokine receptors have NO
intrinsic enzymatic or catalytic activity
what functions in association with NrPTKs?
cytokine receptors
the cytokine receptors do not respond to _______ they only respond to _____.
- GF
- cytokines
what are the 2 kinase families seen in cytokine receptors
- Janus kinase (JAK)
- Src family (Rous sarcoma virus )
binding of integrins to the ECM leads to
dimerization
what is activated by autophosphorylation in integrin signaling?
NrPTK FAK (focal adhesion K)
in integrin signaling Src binds to
FAK phospho-tyrosines
Src phosphorylates FAK on additional tyrosine residues to have them
act as binding sites for downstream signaling molecules
TGF-beta receptor family proteins are known as
protein serine-threonine receptor kinases
type I and type II receptors only bind
TGF-beta
binding of the GF to serine-threonine receptors results in
- clustering of type I & type II receptors
- phosphorylation by type II receptors
the activated type I receptors phosphorylate
Smads
Smads then bind to
co-Smads and enter the nucleus
what are the 4 pathways of intracellular signal transduction?
- cAMP pathway
- phospholipids & Ca2+
- Ras, Raf, MAP Kinase Pathway
- JAK/STAT Pathway
define signal transduction
the cascade of sequential reactions (greatly amplifies the signal)
in signal transduction the binding of 1 molecule of epinephrine induces the synthesis of
many cAMP
an increase in the steps of signal transduction leads to a greater
signal amplification potential
β- adrenergic receptor is ONLY activated by
epinephrine
α-adrenergic receptor is activated by both
epinephrine & norepinephrine
what pathway is initiated by the activation of the β-adrenergic receptor
the cAMP pathway
what pathway is initiated by the activation of the α-adrenergic receptor
inositol-phospholipid-calcium pathway
phospholipase C cleaves
PIP2
what is the function of PIP3?
acts as the 2nd messenger ligand for Ca2+ channels of the ER
after PIP3 is cleaved what remains in the membrane?
diacylglycerol (DAG)
DAG also acts as a __________ and is recognized by…
2nd messenger
protein kinase C
what is an example of a cyclic nucleotide?
cAMP
cAMP is synthesized from ________________ by….
- ATP
- adenylyl cyclase
cAMP is degraded to __________ by…
- AMP
- cAMP phosphodiesterase
cAMP-dependent Protein Kinase A (PKA) is a
tetramer
cAMP-dependent PKA is composed of what subunits?
- 2 regulatory
- 2 catalytic
cAMP binds to the… and causes them to
- regulatory subunits
- dissociate
activated catalytic subunits of cAMP-dependent PKA phosphorylates
serine residues on target molecules
PKA phosphorylation activates a number of important
metabolic enzymes
what is the function of glycogen phosphorylase
- glycogen breakdown
what is the function of glycogen synthase
inhibits glycogen production
an increase in cAMP initiates transcription of target genes that have a specific regulatory sequence…what is the name of these target genes?
cAMP response element (CRE)
the catalytic subunit of PKA enters the nucleus and phosphorylates what transcription factor
CRE binding protein (CREB)
the phosphorylation of CREB leads to the transcription of
cAMP inducible genes
what removes the phosphates added to CREB by PKA ?
phosphatase 1
the catalytic subunit of PKA requires what to get into the nucleus?
NLS
receptor activated PKA phosphorylation is rapidly reversed by
protein phosphatases
- terminate the response
Pi-PLC stands for
phosphoinolsitol phospholipase C
what stimulates the hydrolysis of PIP2 by PLC?
GF & hormones
what are the byproducts of PI-PLC and PIP2?
- DAG
- IP3
DAG stimulates the activation of
protein kinase C
IP3 stimulates the release of
Ca2+ ions from ER
Ca2+ is normally pumped into the
ER
what binds to ligand-gated ion channels?
IP3
DAG remains in the cell membrane to activate PKC family which is a family known for
cell growth
in the PIP3/AkT pathway PIP2 is phosphorylated by
PI3-kinase
PI3-kinase generates what second messenger?
PIP3
PIP3 targets _____ and binds ________.
- Akt
- PDK1
the activation of Akt requires what protein kinase
mTOR
the PIP3/AkT pathway stimulates the activation of
- Bad
- transcription factors
- GSK-3
Bad is responsible for promoting
apoptosis
why is the PIP3/AkT pathway known as a pathway with dual phosphorylation?
b/c it binds both PDK1 & mTORC2
calmodulin is known as the major
Ca2+ binding protein
CaM kinases phosphorylates a large number of
- metabolic enzymes
- ion channels
- transcription factors
CaM kinases are very abundant in the
nervous system
calmodulin contains how many calcium binding sites?
4
what is the target of calmodulin?
Ca2+/calmodulin-dependent kinase
what are 5 methods of Ca2+ regulation in the cell?
- G protein-linked receptor
- Ca2+ channels
- Calcium Pump
- sodium-calcium pump
- ryanodine receptor channel
once released from the ER Ca+ binds to
calmodulin
what stimulates Ca+ release from the ER?
CCK or ACh
an increase of Ca+ initiates what at the pancreatic duct
ZG fusion w/ cell membrane
increase Ca+ triggers
CRAC channel opening
In normal conditions when Ca+ is released what 2 steps proceed?
- trypsin activation in small intestine
- intestinal contents digested
what occurs during the abnormal Ca2+ regulation in pancreatic acinar cells
- excess Ca2+ released activates trypsin within ZGs
- acinar cell/tissues begin to digest
MAP Kinase stands for
mitogen-activated protein kinase
what is known as a major pathway in cellular signaling that is highly conserved in eukaryotes?
MAP kinase pathways
MAP kinases are composed of serine/threonine kinases that respond to
hormones/GFs
MAP kinase pathways regulate
cell growth & differentiation
what are the 2 families included in the MAP kinase pathways?
- ERK
- MEK
Ras responds similarly to
α subunit of G-protein
Ras was first identified as a
rat oncogenic protein caused by a virus
Ras mutations in cancer cells results in a
continually active GTP-bound state
what stimulates the exchange of GTP for GDP when activating Ras?
guanine nucleotide exchange factors (GEFs)
what terminates Ras activity?
GTP hydrolysis
the termination of Ras through GTP hydrolysis is stimulated by
GTPase-activating proteins (GAPs)
what was the first evidence that the action of mutated genes can cause cancer?
Ras (rat sarcoma virus)
what organizes the ERK & upstream activators of the MAP cascade?
scaffolding proteins
what is an example of a scaffolding protein?
KRS
KRS signaling cassette ensures the specific & efficient activation of
MEK -> ERK
ERK dissociates from KSR and then
translocates to the nucleus
JAK stands for
janus kinase
STAT stands for
signal/transducers and activators of transcription
STATs are a family of….. w/ ________ domains
- 7 transcription factors
- SH2 domains
what recruits STATs
cytokine receptor stimulation
STATs are translocated to the ___________ and stimulates…
- nucleus
- transcription of target genes
what happens to the receptors for TGF-β after ligand binding?
type I & type II receptors associate
how does phosphorylation of TGF-β receptors happen?
type II phosphorylates type I
activated type I receptors in the TGF-β activate what specific types of proteins?
Smad
Smads complex w/ other Smads & translocate to the nucleus where they regulate
gene expression
TGF-β/Smad pathway is involved in
wound healing
what are the 5 types of signaling networks?
- negative feedback
- positive feedback
- feedfoward relay
- stimulatory crosstalk
- inhibitory crosstalk
explain a feedfoward signaling network
maintains pathway going & also effects downstream products
explain the stimulatory crosstalk of a signal network
the product of one pathway stimulates the product of another pathway
what is an example of crosstalk between pathways?
ERK & PI3-Kinase signaling pathways
continue the flow ras/raf-> _________ -> __________
- MEK
- ERK
continue the flow PI3-kinase -> _________ -> _________ -> ________
- Akt
- TSC2/TSC1
- mTORC1
Akt can also inhibit
Ras/Raf complex
