Signal Transduction 2 Flashcards
EnZ linked receptors include
Tyrosine kinase linked
serine/threonine kinase-linked
Protein phsphatase-linked
Guanylyl cyclase linked
Two forms of Tyrosine kinase linked receptors
single protein w/ 1 transmembrane domain that dimerizes upon ligand binding
receptor has 2 subunits to form a tetramer upon binding
Tyrosine kinsae receptors have intrinsic
tyrosine kinase activity upon phosphorylation
EGF tyrposine kinase receptor is inactive as;
active as:
inactive a monomer
active as dimer
PDGF tyrosine kinsase receptor is incative as:
active as:
inactive as: monomer
active as: dimer
Insulin receptor is a tyrosine kinase receptor that is inactive as:
active as:
inactive as dimer
active as tetramer
Each TK receptor has ______ domain with tyrosine kinase activity
cytoplasmic
Activation of Tyrosine Kinase receptors is dimerized and activated by:
Trans-autophosphorylation
One dimer is activated by phosphorylation, it in turn phosphorylates the other unit back. Concept is called
Trans-autophosphorylation
After trans-autophosphorylation we bind:
intracellular molecules
Tyrosine kinase receptors are key for:
-regulation of cell proliferation and differentiation
ligands of tyrosine kinase include:
hormones like insulin
GFs like EGF, PDGF and VEGF
What receptors play imporant role in onogenesis and are targets of chemotherapies
Tyrosine kinase receptors
Receptors are first part of signal transduction and provide
specificiy
Receptors and their ligand are key, but we need what other guys to transduce a signal through cytoplasm into nucleus
intracellular signal molecules
G proteins Second messengers Proteins kinases and Protein phosphates Transcription factors are all examples of:
Intracellular signal molecues
Examples of intracell signal molecules
G proteins
Second messengers
Proteins kinases and Protein phosphates
Transcription factors
proteins that bind DNA and regulate transcription of gene
Transcription factors
CREB is :
cAMP response element biding protein
ubiquitous TF that activates many differnt genes
ubiquitous TF that activates many differnt genes
CREB
Myc, Fos, Jun are examples of
transcripion factors
What two things do signal transduction cascades regulate as far as TFs are concerend
Regulate it’s nuclear translocation and it’s ability to bind to DNA
What Regulates TF’s nuclear translocation and it’s ability to bind to DNA
signal transduction cascades
What do activated transcription factors do?
induce transcription by activating RNA polymerase–> get transcription of mRNA from target gene
Why do we want TF to activate RNA polymerase
bc then it will transcribe mRNA of target gene
Trend of TF;s is:
P’d by Protein Kinases will:
de-“d by protein phosphorylses will:
PKs will activate
PPs will inactivate
What aa do Protein kinases like to add P’s to
ser/threonine/tyrosine
PKA, PKC, Ca/calmodulin dependent kinase and MAP kinases are examples of
Serine/threonine specific PK’s
Tyrosine kinase-linked receptors like EGF and cytoplasmic kinases like Src and Abl are spefic for which protein kinase
Tyrosine specific
What kinases have dual specificiy and phosphorylate both tyrosine and threonine
MAP kinase kinases
The activity of a protein is often regulated by one/many kinases and phosphorlyases acting on a protein
MANY
What regulates activity of kinases and phosphatases
via second messengers
what does a protein kinase need to do it’s job
ATP
Phosphorylate protein is likely to
interact with dif effectors (more likely to then the d’Pd guy)
Small diffusible molecules generated in response to ligand-receptor interaction
second messengers
Second messengers will:
activate downstream effectors
cAMP is made when:
alpha sub activates adenylyl cylase : will will convert ATP–> cAMP
how does activated adnelylyl cyclase make cAMP
ATP–> cAMP
what does cAMP do?
acitates PKA
what activtes Protein kinase A
cAMP from activated adenylyl cyclase
DAG and IP3 are examples of
second messengers
How is DAG and IP3 made
Alpha-q will turn on Phospholipase C (PLC)–> PLC cleaves PIP2 to generate DAG and IP3
What do we generate from PIP2 and what enZ does this?
DAG + IP3 via PLC (acivated by alpha-q)
What does DAG do
activaes protein kinase C
What turns on protein kinase C
DAG
What does IP3 do?
IP3 binds to IP3 receptors on ER–> cuases Ca+ release
What will cause Ca+ release from ER
IP3 binding to IP3 receptors
Ca++ is a type of
secondary messenger
how do we generate Ca++
opening ion channels
What does Ca++ do intracellularly
binds to pretins and activates PKC adn other kinases and enZs
cAMP binds to what units on PKA
binds to the R subunits and relases the active catayltic subs
how mand cAMP’s does an adenylyl cylcase generate once activated?
MANY
cAMP will result in _______ of signals
amplification
What will phosphorylate CREB
PKA that was turned on by cAMP that was made from adenylly cylclase
What will inhibit or turn off cAMP pathway
when aplha–i binds to adenylyl clycase and turns it off
Metabolites of phospholipids activate:
Protein Kinase C
GRPrs coulpled to _______ regulate the Inosotol-lipid pathway
G-alpha-q
Pathway to activate DAG
Ligang–> to GPCR which then activates G-alpha-q via GTP binding–> PLC is actiaved via Galphaq–GTP binding
What does PLC do
cleaves PIP2 into IP3 and DAG and DAG stays in membrane to activate PKC while IP3 goes on to release Ca+ from ER
Ras, Rho, Rac, Rap and Rab are examples of
Monomeric G proteins
these guys are activated by interacting w/ proteins known as guanine nucleotide exchange factots
Monomeric G proteins
small molecular wt proteins, small GTPases and small GTP binding proetens or p21s are
Monomeric G proteins
These guys are inactivated by interacting with proteins known as GTPase activating proteins
monomeric G proteins
Monomeric G proteins are inactivated by interacting with proteins known as
GTPase activating proteins or GAPs
KEy difference between hetertrimeric G proteins and monomeric G proteins
heterotrimeric activated by interactions with GPCR
monomeric activated by interaction with GEF
A guanine nucelotide exchange factor is a
GEF
This will activated mononumeric G proteins
GEF
SOS is an example of a
GEF
How are GEFS activated
when they are recruited to activated tryosine kinase linked receptors by adaptor proteins like GRB2
process of activating GEF
ligan binds to dimerized tyrosine kinase receptor–> this will cause phosphorylation of an Adaptor–>The adaptor will then activate guanine nucleotide exchange factor
GRB2 is an example of
an adaptor protein that will recuite GEF
What happens when a GEF interacts with Ras-GDP
makes it release GDP and bind a GTP = Ras-GTP
What does Ras-GTP do? how did it get the GTP
Ras-GTP will bind and singal other molecules
it got the GTP bc a GEF made it lose the old GDP and bind a GTP
How can Ras go from Ras-GTP to Ras-GDP
it has intinisic GTPase activity
How does Ras know when to hydorlyze it’s GTP?
Ras-GTP will associate with GAP (a GTPase activating protein) that induces Ras to hydrolyze it’s GTP
What does GAP do
makes Ras-GTP hydorlyze it’s phosophate by activting the intrinsic GTPase activity Ras has
Monomeric G proteins key for this signaling cascade
MAP or mitogen activated protein kinase sidnaling cascade
How does the MAPK pathway work
Start with activationg of monomeric G protein–> activates MAP KKK–> P’s and activates MAP KK–> Ps and activates MAP kinase–> P the transcription factor
Another way to phrase the MAPK pathway
Ras-GTP gets a new GTP from GEF Ras-GTP activates Raf Raf P's MKK1 MKK1 P's ERK ERK phosphorylates lots of TF's
What is teh end result of the MAP kinase pathway
ERK gets’s P’d by MKK and will then phosphoyrlate a bunch of Transcription facots
Mutations in this receptor can cause tumors that have abnormally high activity to promote tumorgenesis and metastasis
EGF receptor and Ras
Mutation in EGF or Ras
promote tumorgenesis and metastasis
What’s good cancer chemotherapeutic
agents inhibiting the signal by EGF receptor
Gefeitinib and Erlotinib are used:
as tryosine kinase inhibitors by inhbiting singaling of EGF
Efficiacy of Gefetinib and Erlotinib are enhanced by
presence of mutations on EGF receptor
Gefetinib and Erlotinib decrease ________ in 80% patiens with mutated EGF receptor
lung tumor burden
How well do gefetinib and Erlotinib work on patients without receptrion mutations in EGF?
only 10% help
Population of individual more suspecitlbe to EGF receptor mutation leading to lung cancer (non-smoking induced)
Asian females with adenocarcinoma
Cells need to be able to turne exctracell signals off, or there would be:
uncontrolled signaling
Constituitive and uncontrolled signaling contributes to
cancer
Many ______ are mutated signal molecules with promote uncontrolled, ligand-independent signaling
Oncogenes
Turning off the signal
attenuation
Attetuation
turning off signal at all levels each activated signal must go back to inactive state
How do we accomplish attenuation
ligan inactivation or dissociation from receptor receptors dissocatie from proteins Adaptor protein complexes dissociate G protesin hyrodlyze GTP to GDP Phospholyrlyation is done or undone metabolize 2 messenger ions sequesterd or pumped out
Receptor mediated endocytosis is:
Adaption
OCcurs when signaling system responds to intensity and frequency of stimulation; response is proportion to stimulus
Adaption
If there is no ligand, receptors may:
not be localized in specific location on plasma membrane
receptor mediated endocytosis to regulate number or amount of receptors that respond to signal
can promote degradation of both receptor and ligand
Adaption–because it’s induced by the binding of ligand to the receptor
How does endocytosis of ligand-receptor complex occur
This is adaption
Done by migration of complexes to electron dense region of membrane coated in clathrin
What happens once a receptor-ligand complex is engulfed in clarthin coated pit?
bind to CURL = vesicles with low pH that favor dissociation of the ligand from receptor
Retroendocytosis
process of recycling ingested receptors
Free receptor located in CURL can:
be recycled or
degraded
Receptor desensitization is a form of
Adaption
In ________ desensitization, signaling by stimulated receptor is attenuated
HOMOLOGOUS
This occurs due to covalent modification of ligand-bound receptor
Homologous desensitization
In receptor desensitization, signaling by the ______ is attenuated
stimulated
basically receptor gets stimulated, gets signaled to get phospohrlyed, then something binds to it, so as a reslt of it’s signaling, it gets blocked from signaling
In _______ desensitization, signaling by both the stimulated receptor and by other teypes of receptors is attenuated
heterologous
What receptors are blocked in heterologous desensitization
stimulated and unstimulated
Why does heterologous desensitization occur?
covalent modification of receptors and other processes such as competion for shared second messenger
