Receptors and Cancer Flashcards Preview

MCM > Receptors and Cancer > Flashcards

Flashcards in Receptors and Cancer Deck (48):

Slow response

change in amounts of proteins by change in expression of genes

needs to go to nucleus first


Fast response

change in activity or function of enzymes or proteins

ex: changes in metabolism, PK, PFK2, glucagon/insulin pathway


Signaling Cascades

Signals (ligands)-secreted by exocytosis

Receptors- bind specifically to signal molecules

Effectors: targets of receptors inside cells, alter activity of different proteins and make 2nd messengers
ex: Ca and cAMP


Endocrine Signaling

long distance signaling

-signal reaches blood stream and then travels to distant target tissue/cells
-freely diffusible signals
-long lasting-takes time to go through the circulatory system

ex: hormones


Paracrine Signaling

acts locally

-affects nearby cells but not as freely diffusible
-short lived

ex: neurotransmitters (Glu)


Autocrine Signaling

cells respond to signals that they themselves release or they release cells of the same type

cell secretes signal that feeds back and binds to receptor on own surface

ex: growth factors on cancer cells


Direct/Juxtacrine signaling

-bring cell to them

ex: phagocyte engulfs bacteria/virus and delivers to B or T cell for immune function


Same ligand-different response

some ligands can create different responses in different target cells

ex: acetylcholine:
heart- causes relaxation
muscle- contraction
salivary gland- secretion of saliva



hormone that produces satiety, or the feeling of fullness

message sent to hypothalamus to stop eating

if deficient, keep eating = obesity


G-protein coupled receptors (GPCRs)

G-alpha, beta, and gamma units

1. ligand binds to receptor
2.conformational change of receptor, G protein binds to receptor
3. alpha subunit binds to receptor, GDP swapped for GTP which activates Galpha
4. alpha breaks off from beta and gamma
5. Galpha is active and binds to and activates effector molecule (membrane bound)
-Adenylyl Cyclase which catalyzes cAMP formation from ATP
-PLC which catalyzes DAG and IP3 formation


Adenylyl Cyclase and cAMP

Adenylyl cyclase generates cAMP by converting ATP to cAMP

cAMP targets PKA (has 4 subunits)

PKA then phosphorylates other proteins


Cholera epidemic

toxin gets into gut, causes G-alpha,s to remain active with GTP

this leads to a large increase in cAMP and thus an increase in PKA

PKA phosphorylates CFTR Cl channel which causes a large Cl secretion to outside the cell and doesn't allow resorption either

this leads to an influx of water, leads to diarrhea


Desensitization of Signal

potentiate - turn up
attenuate - turn down (attenuate for what!!)

1. Hormone levels drop: decreased adenylyl cyclase = decreased cAMP = decreased PKA

2. Remove signaling molecule: phosphodiesterases remove cAMP and cGMP

3. Receptor sequestration: via endosome, remove from membrane, can return or..

4. Receptor destruction: endosome removes receptor and takes to lysosome for destruction


G protein receptor kinases (GRKs)

phosphorylates GPCR so arrestin can bind to 3rd intracellular loop

this prevents Galpha from binding and thus Galpha does not get activated and there is no downstream affects


G-alpha types

G-alpha-S: stimulatory, activates AC and then cAMP....

G-alpha-I: inhibitory, inhibits AC and thus stops pathway

G-alpha-Q: activates PLC (phospholipase C), which creates DAG and IP3 formation


Nuclear Hormones

are hydrophobic

diffuse through membrane to nucleus hormone receptor to be transcribed in the nucleus


Signaling Molecules

-steroid hormones-progesterone, testosterone
-thyroid hormone-thyroxine

Hydrophilic: eg. growth factors
-amino acid derived-histamine, serotonin, epinephrine
-from lipid metabolism-acetylcholine
-polypeptides-insulin, glucagon,...


Intracellular receptors

ligand-binding domain
DNA-binding domain
Transcription-binding domain


Hydrophobic ligands

vitamin D3
retinoid acid

look for OH groups


Retinoid Acid

derived from Vit A

excess retinol (vit A) leads to abnormalities

retinal=active form

accutane for acne


2 Hit Hypothesis

2 errors to end up with cancer

inherit one "hit" or mutation and this means that you only need one more mutation to cause a disease like cancer

if you start with one, you are more likely to get cancer by accumulating another error
first error normally inherited
2nd is typically epigenetic, more dynamic

1st hit: DNA repair present to fix mutations,
P53, RB, APC, all tumor suppressors, all involved in DNA repair to check for errors (halt division until repair is doing job)
if mutation is in these, may not get repaired

2nd hit: oncogene,


Cell Growth/Division

Cell cycle and apoptosis occurring
Tumor suppressors working

but when a mutation or error occurs: oncogene

Oncogene (growth genes)
tumor suppression avoided
uncontrolled proliferation


Tumor Suppressors

p53, BRCA1/BRCA2, APC, Rb



RAS, HER2 (an RTK), EGF receptor (an RTK)


Enzyme Coupled Receptors

Tyrosine Kinases
JAK-STAT Receptors
Ser/Thr kinases

all create docking site for other proteins


Receptor Tyrosine Kinases (RTKs)

used for response to growth factors!!!!

in the cytoplasmic tail

-ligand binds
-causes conformational change in receptor and inducing dimerization of 2 monomer receptors
-Autophosphorylation occurs to act as scaffold
-phosphotyrosine binds to SH2 domain of Grb2
-SH3 domain of Grb2 binds to SOS
-SOS binds to Ras (monomeric G protein-small GTPase)
-Ras binds to Raf (MAP kinase, kinase, kinase), cascade affect
-Raf to Mek to Erk (progress down pathway by phosphorylation) = gene transcription thru this pathway

(Ras first discovered human oncogene)


Growth Factors

named after the tissue they were discovered in

EGF - epidermal
PDGF - platelet derived
FGF - fibroblast
IGF-1 - insulin-like
NGF - nerve


Insulin Signaling

RAS dependent:
-uses Grb2
-slower because makes alterations in gene transcription
e.g. increased transcription of glucokinase = glycog synth

RAS independent:
-uses PI3-kinase
-faster because changes enzyme/protein activity
e.g. increased GLUT 4 movement = increase glycog synth


JAK-STAT Receptors

receptors bind cytokines, receptors dimerize, bind JAKs

JAKs phosphorylate each other (autophosphorylate)

receptor binds and phosphorylates STATs

STATs (transcription factor) dissociate from receptor, dimerize, translocate to the nucleus


Serine-Threonine receptors & Smad

R-Smad: receptor specific Smad and forms complex with Co-Smad (common Smad)


Activation of Cell Cycle

Myc activation from MAP Kinase (Erk)

Active G1CDK
(CDK-cyclin dependent kinase)

Rb is inactivated via phosphorylation and allows E2F to be activated

active E2F will activate G1S/-CDK and S-CDK and all 3 of these will positively feedback to create more E2F

once there is enough E2F, DNA synthesis (S-phase) can begin


Cell Cycle

M-mitotic phase, cell division

interphase-long growth period and includes:
-Gap 1 (G1) phase
RNA and protein synthesis needed for DNA replication

-DNA synthesis (S) phase

-Gap 2 (G2) phase
DNA stability is checked

-G0, when conditions not appropriate, cells arrest here, as we age, stuck in G0


Restriction and Checkpoints

Restriction point (R)- occurs if growth factors are limiting

G1 checkpoint
-correct any DNA damage (chemical modifications)

G2 checkpoint
-verify completeness

Metaphase checkpoint
-ensure chromosomes are attached to mitotic spindle



Rb protein is major regulator or cell cycle/apoptosis

active = hypophosphorylated
inactive = hyperphosphorylated

S-phase requires E2F transcription factors Cyclin E and Cyclin A (both activate CDK2, keep Rb inactive/E2F active)


Cyclin dependent kinases (CDKs)

binding of cyclin to CDKs partially activate them
-full activation requires CDK-activating kinase (CAK)

p27: CDK inhibitor (CDKI)
-binds to cyclin-CDK complex to inactive kinase activity
-using p27 is a slow step because it needs to be transcribed


Cyclin-CDK activity

G1/S transition phase: Cyclin E-CDK2

S phase: Cyclin A-CKD2

M-phase: Cyclin A-CKD1



Inhibits CDK by phosphorylating "roof" site


Cdc25 (phosphatase)

dephosphorylates "roof" site to increase CDK activity


p27 vs. kinase-phosphatase pathways

p27 is a CDKI (inhibitor) and attaches to the active CDK to inactive its kinase activity

Wee1 is kinase that phosphorylates the CDK to inactivate it
Cdc25 is a phosphatase that dephosphorylates the phosphate to make CDK active again



targets S-cyclins and M-cyclins

inactive APC/C is activated by binding to Cdc20

cyclins destroyed, inactivates most CDKs,
CDK's dephosphorylated


p53 (tumor suppressor)

guardian of the genome, transcription factor

p53 promotes apoptosis

p53 promotes cell cycle arrest/DNA repair



is an intracellular proteolytic cascade

intrinsic and extrinsic pathway

Intrinsic: mitochondrial dependent
-BAX/BCL are both key regulators

Extrinsic: mitochondrial independent


Intrinsic Pathway, Apoptosis

cytochrome-c is released from the mitochondria and binds to Apaf1 (procaspase-activating adaptor protein)

Apaf1 forms an apoptosome which then activates caspase-9 (initiator caspase)

Caspase-9 activates caspase-3 (executioner caspase)

BAX: activates/promotes apoptosis
BCL2: inhibits apoptosis by inhibiting BAX


Extrinsic Pathway, apoptosis

Fas binds to Fas death receptor

FADD activates Procaspase 8, activates caspase 3 for apoptosis

TNF-alpha binds to receptor, TRADD activates procaspase 8, activates caspase 3 for apoptosis


BRCA (tumor suppressor)

responds to DNA damage

stops replication if damage is noted


Chronic Myelogenous Leukemia (CML)

BCR-ABL fusion protein



mutated RTK, constant proliferation



similar to Ras

when activated, results in ligand independent signal transduction

mutation occurs during viral replication!!

see correlation box