Signal Transduction 2 Flashcards by Meghan May

EnZ linked receptors include

Tyrosine kinase linked
serine/threonine kinase-linked
Protein phsphatase-linked
Guanylyl cyclase linked

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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

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Tyrosine kinsae receptors have intrinsic

tyrosine kinase activity upon phosphorylation

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EGF tyrposine kinase receptor is inactive as;

active as:

inactive a monomer

active as dimer

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PDGF tyrosine kinsase receptor is incative as:

active as:

inactive as: monomer

active as: dimer

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Insulin receptor is a tyrosine kinase receptor that is inactive as:
active as:

inactive as dimer

active as tetramer

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Each TK receptor has ______ domain with tyrosine kinase activity

cytoplasmic

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Activation of Tyrosine Kinase receptors is dimerized and activated by:

Trans-autophosphorylation

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One dimer is activated by phosphorylation, it in turn phosphorylates the other unit back. Concept is called

Trans-autophosphorylation

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After trans-autophosphorylation we bind:

intracellular molecules

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Tyrosine kinase receptors are key for:

-regulation of cell proliferation and differentiation

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ligands of tyrosine kinase include:

hormones like insulin

GFs like EGF, PDGF and VEGF

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What receptors play imporant role in onogenesis and are targets of chemotherapies

Tyrosine kinase receptors

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Receptors are first part of signal transduction and provide

specificiy

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Receptors and their ligand are key, but we need what other guys to transduce a signal through cytoplasm into nucleus

intracellular signal molecules

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G proteins
Second messengers
Proteins kinases and Protein phosphates
Transcription factors 
are all examples of:

Intracellular signal molecues

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Examples of intracell signal molecules

G proteins
Second messengers
Proteins kinases and Protein phosphates
Transcription factors

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proteins that bind DNA and regulate transcription of gene

Transcription factors

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CREB is :

cAMP response element biding protein

ubiquitous TF that activates many differnt genes

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ubiquitous TF that activates many differnt genes

CREB

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Myc, Fos, Jun are examples of

transcripion factors

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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

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What Regulates TF’s nuclear translocation and it’s ability to bind to DNA

signal transduction cascades

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What do activated transcription factors do?

induce transcription by activating RNA polymerase–> get transcription of mRNA from target gene

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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