TOPIC B: Cell signalling Flashcards
What does amplification mean
The number of affected molecules increasing geometrically due to a signalling cascade
What are the 4 types of signalling + basic description
Contact dependent: cells in contact
Paracrine: released to neighbouring cells
Synaptic: Neurotransmitters at a synapse
Endocrine: hormones in bloodstream
What are the 3 main classes of hormones + basic description
polypeptide/protein: Stored in secretory vesicles
amide hormones: developed from tyrosine like epinephrine and norepinephrine
steroid hormones: steroids similar in structure (cholesterol)
What are the two main types of molecular switches + basic description
phosphorylation: kinase and phosphatase deactivate or activate
binding of GTP: exchange of GDP for GTP activates.
What are the 2 broad types of receptors
Cell surface receptors
Intracellular receptors
What are the 3 types of cell surface receptors
Ion channel coupled receptor
G protein coupled receptor
Enzyme coupled receptor
What is the 1 type of intracellular receptor
Nucelar receptor
What is an enzyme linked receptor
cell surface receptors linked intracellular enzymatic activity. Trigger a cascade.
What are the 2 types of enzyme linked receptors studied in this course
receptor tyrosine kinases
tyrosine kinase associated receptors
Describe activation of a receptor tyrosine kinase
when activated phosphorylate intracellular Tyr residues.
RTKs dimerise and then trans auto phosphorylation occurs.
Phosphorylation of tyrosine kinase domain acts as docking sites.
What is a domain of a docking, adaptor or scaffold protein
Specific parts of protein which recognise certain regions on other proteins.
Define a docking protein
Proteins embedded in the cell membrane, allows other proteins to dock to them
Define an adaptor/scaffold protein
Protein that links/bridges one protein to another if they cannot bind to the receptor themselves. Allows further activation
Explain the complex formed at the insulin receptor
insulin receptor is a receptor tyrosine kinase.
IRS1 binds when it is phosphorylated which allows other proteins to attach and become activated.
Describe the MAPK pathway of a receptor tyrosine kinase
Insulin RTK activated causing binding of IRS1.
Grb2 binds to IRS1 allowing Ras-GEF (Sos) to bind and become activated.
Sos activates Ras protein by GDP/GTP exchange.
Ras activates Raf. Raf activates Mek which activates Erk by phosphorylation.
Erk phosphorylates proteins causing cell proliferation/growth/differentiation
Describe the PI3K/Akt pathway of a receptor tyrosine kinase
Insulin RTK activated causing binding of IRS1.
PI3K binds activating it, causing it to phosphorylate docked inositol phospholipids.
This allows protein kinase 1 to dock and with protein kinase 2 phosphorylate and active Akt.
Akt causes multiple cell responses explained in different question
What are the cell responses due to Akt activation
Phosphorylates Bad causing dissociation and activation of Bcl2 causing cell survival.
Protein synthesis, glycogenesis, gluconeogenesis, lipogenesis in liver
GLUT4 translocation and glycogenesis in muscle
GLUT4 translocation, lipogenesis in adipose
What is a tyrosine kinase associated receptor
Enzyme linked receptor that couple to proteins that have Tyr kinase activity.
Outline the activation of cytokine tyrosine kinase associated receptors
Cytokine binds causing dimerisation of receptors
JAK protein already attached to monomers is then activated causing them to phosphorylate each other and then the receptor.
This provides binding sight for STAT proteins which then form complex that travels into the nucleus and activates transcription.
Describe a ligand gated ion channel
A cell surface receptor also called an ion channel coupled receptor.
open or close in response to a ligand
Outline the physical characteristic of a GPCR
Cell surface receptor
7 transmembrane segments
extracellular N, intracellular C
Define a G protein
guanine nucleotide binding proteins act as molecular switches by binding GTP to other proteins in the cell
What enzymes activate and deactivate a G protein
Guanine nucleotide exchange factor (GEF): swaps GDP for GTP, activates
GTPase activating protein (GAP): hydrolyses GTP to GDP, deactivates
Describe the trimeric complex of a G protein
alpha, beta and gamma units.
alpha unit works on its own as a GTPase
Beta and gamma work together
Explain the activation of a G protein from a GPCR
GPCR activated by signalling molecule
GPCR interacts with G protein
G protein ejectes GDP for GTP, causing activation and releases beta gamma unit.
unit activates other proteins delivering message throughout cell
turned off when GTP is hydrolysed to GDP.
Define an effector enzyme and a second messenger
Effector enzyme:
More enzymes activated by a G protein or earlier protein in pathway
Second messengers:
affect later parts of pathway and are activated by effector enzymes
Explain the activation of the inositol phoshpolipid GPCR pathway
GPCR activated causing activation of G protein
beta gamma unit activates phospholipase C (effector enzyme in membrane)
phospholipase C cleaves PIP2 into DAG and IP3 (second messengers)
IP3 targets Ca channels of E.R causing Ca release
Ca and DAG activate protein kinase C which activates cell response
Explain the activation of the cAMP GPCR pathway.
GPCR and G protein activated
unit activates adenyl cyclase to convert ATP to cAMP (second messenger)
cAMP activates protein kinase A by binding to catalytic subunits, goes onto activate cell response
Briefly explain how adrenaline and GPCR causes glycogenolysis
adrenaline activates GPCR and G protein
cAMP pathway activates glycogen phosphorylase
Briefly explain how adrenaline and GPCR causes increased gene transcription.
adrenaline activates GPCR and G protein
cAMP pathway activates molecules for gene transcription to move into the nucleus
Outline the stimulation pathway for cortisol production
ACTH release from anterior pituitary in response to CRH from hypothalamus.
Stimulates cortisol production pathway in adrenal cortex
Describe cushins syndrome
chronic exposure to cortisol causes decreased growth in children, weight gain, hypertension, diabetes, osteoporosis.
Treatment includes adrenalectomy or steroid replacement
What are the three main types of steroid hormones and the examples of them produced in the cholesterol pathway
Mineralocorticoids
Glucocorticoids
Androgens
What are the three main types of steroid hormones and the examples of them produced in the cholesterol pathway
Mineralocorticoids: Aldosterone
Glucocorticoids: Cortisol
Androgens: Testosterone
What is a nuclear receptor
An intracellular receptor activated by lipophilic ligands as they can diffuse across cell membrane.
Describe the mechanism of nuclear receptor action
Ligand activates nuclear receptor
induces homo or hetero dimerisation as well as binding of dimer to DNA
Coactivator recruitment increases target gene transcription by binding to nuclear receptor
Altered levels of the hormone regulated gene product produce cellular response
What are the 2 types of estrogen receptors
alpha and beta
What is ERalpha important for
Female reproduction
mammary gland function
bone, CVS, brain
What is ERbeta important for
ovary, bone, brain, male prostate
Outline a selective estrogen receptor moedulator (SERM)
Mimic estrogen receptor ligands to help treat disease
ER agonist is BPA, stimulates over transcription causing birth defects
ER antagonist if tamoxifen, which treats breast cancer, by binding to ER, preventing ER mediated gene transcription
Briefly describe chronic myeloid leukaemia
caused by oncogenic tyrosine kinase called BCR-ABL
overproduction and overflow of immature WBC and uncontrolled cell growth and proliferation
Gleevec binds BCR-ABL preventing ATP from binding
Briefly explain monoclonal antibodies
Can target cell surface receptors to stop disease by binding to receptor instead of ligand.
Herceptin can bind to HER2 inhibiting activation of signalling pathways. Can be used to treat HER2 positive breast cancer.
