Topic 11 Flashcards
4 steps to cell signalling
- signalling molecules released (ligands)
- recognition of signalling molecule by target cell (receptors)
- signal transduction; signalling cascade (conversion of extracellular signal into intracellular instructions)
- final impact on target cell and subsequent impact on organism as whole
Cell communication and signal transduction __________ in complexity with multicellular organisms
increases
modes of signalling
- cell to cell
- paracrine (neurotransmitters across a synapse)
- endocrine (hormones)
- autocrine
5 classes of ligands
- steroid hormones
- eicosanoids
- neurotransmitters
- peptide hormones and polypeptide growth factors
- simple gases
steroid hormones
- hydrophobic molecules that can diffuse across cell membrane and bind to intracellular receptors
- estrogen, glucocorticoids
steroid hormones mode of action
endocrine, paracrine, and autocrine
eicosanoids
-hydrophobic, rapidly broken down that bind to cell surface receptors
eicosanoids mode of action
paracrine or autocrine
neurotransmitters
-hydrophilic and bind to cell surface receptors
neurotransmitters mode of action
endocrine, paracrine, and autocrine
peptide hormones and polypeptide growth factors
- largest and most variable, primarily hydrophilic and cannot cross cell membrane but bind to cell surface receptors
- insulin, epidermal growth factor
peptide hormones and polypeptide growth factors mode of action
endocrine, paracrine, and autocrine
simple gases
-passive diffuse across membrane, bind directly to enzymes and do not use receptors
simple gases mode of action
paracrine
two classes of receptors
intracellular and cell surface
nuclear receptor superfamily
intracellular receptors that primarily function as transcription factors
-glucocorticoids, thyroid hormone
3 types of cell surface receptors
- g-protein coupled receptors (integral membrane protein)
- receptor protein tyrosine kinases (integral membrane protein)
- cytokine receptor superfamily (peripheral membrane protein)
cytokine receptor superfamily function together with..
non receptor protein tyrosine kinases
glucocorticoid action
- inactive when bound to a chaperone
- become active when bound to the ligand
dimer
two active receptors that translocate to nucleus and associate with co-activator protein HAT
active gene transcription
glucocorticoid receptor + ligand + HAT coactivator
gene regulation by thyroid hormone receptor
- receptor (dimer) bound to DNA with or w/o ligand
- w/o ligand receptor binds corepressor HDAC to repress gene transcription
- hormone binds receptor changing conformation to disassociate from HDAC and associate with coactivator HAT allowing gene transcription
g-protein coupled receptors
largest family of cell surface receptors and are transmembrane proteins with multiple transmembrane domains
g-protein
transmits G protein coupled receptor signals to intracellular targets via intermediary protein
When extracellular receptor domain binds the ligand of g-protein coupled receptors
causes a conformational change activating a G protein. alpha subunit of G protein dissociates from beta and gamma to carry signal to intracellular target
adenylyl cyclase
intracellular target molecule
tyrosine kinase receptors
- plinked ot intracellular enzymes
- one transmembrane domain
- enzyme activity by intracellular domain of receptor or separate protein associated with intracellular domain
how are tyrosine kinase receptors activated
by phosphorylating tyrosine residues on both receptor and target substrates which can then associate with downstream targets and initiate a signalling cascade
What proteins can recognize tyrosine kinase receptors?
-insulin and multiple growth factors
how do tyrosine kinase receptors change when activated?
dimerization followed by phosphorylation
non receptor tyrosine kinase
associate with receptors that contain no catalytic activity
intracellular signal transduction
chain of reaction that transmit chemical signals from cell surface to their intracellular targets (signalling cascade)
4 pathways of intracellular signal transduction
- 2 indirectly connected ti transcription factors (cAMP and MAP kinase)
- 2 directly coupled to transcription factors (Notch signalling and Wnt pathway)
cAMP
cyclic AMP is an important second messenger associated with G protein coupled receptors and is important for response of cells to variety of hormones
A phosphate group in cAMP is covalently bound to both the 3’ and 5’ carbon atoms by the enzyme….
adenylyl cyclase
second messenger
a compound that is modified as a result of ligand-receptor interaction and relays message from receptor to target
-can be used in multiple pathways
adenylyl cyclase
an enzyme that catalyzes formation of cAMP from ATP; stimulated by alpha subunit of activated G protein
cAMP phosphodiesterase
an enzyme that degrades cyclic AMP
The second messenger _____ initiates intracellular transduction
cAMP
regulation of protein kinase A
cAMP binds to cAMP dependent protein kinase called protein kinase A (PKA) causing dissociation of PKA regulatory subunits and it phosphorylates downstream target proteins
PKA and CREB
PKA activates transcription factor CREB by phosphorylation; CREB recruits coactivators and initiates transcription at CRE binding sites
CRE
specific DNA binding element that is in the promoter region of cAMP responsive genes
PKA and glycogen
In regulation of glycogen metabolism, PKA phosphorylates two target enzymes; activates phosphorylase kinase and inhibits glycogen synthase
cAMP signaling pathways can effect both…
transcription factors and metabolic enzymes
PP1- protein phosphatase 1
counterbalances PKA activity to fine tune the signalling mechanism
A single receptor can activate_______ G proteins
multiple
1 hormone molecule binding 1 receptor can activate ____ target proteins.
many
MAP (mitogen activated protein) kinase
cell surface receptors linked to enzymes to produce intracellular signals
MAP kinase pathways can be associated with…
both receptor and nn receptor tyrosine kinases
MAP kinases are activated in response to…
a variety of growth factors and other signalling molecules
stereotypical MAP kinase pathway
Ras-Raf-MEK-ERK
Raf
rapidly accelerating fibrosarcoma; a protein serine/threonine kinase that is activated by Ras and leads to activation of ERK MAP kinase
ERK
extracellular signal-regulated kinase
MEK
map kinase/ERK kinase; dual specificity protein kinase that activates members of ERK family by phosphorylation of both threonine and tyrosine residues
Ras
rat sarcoma; guanine nucleotide-binding proteins that function analogously to alpha subunits of G proteins alternating between inactive GDP-bound and active GTP bound forms; integral membrane lipoprotein
___ could be directly linked to growth factor induced cell proliferation
Ras
one of the first oncogenes identified in human cancers
Ras
GEF
guanine exchange factor; activates Gas
mutated Ras
locked in GTP binding form
GAP
guanine activating protein; terminates Ras activity
intermediate protein
links phosphorylated region of tyrosine kinase with other target molecules
notch signalling
example of cell to cell signalling;
- notch receptor receives signal from delta ligand on surface of an adjacent cell
- this activates gamma-secretase enzyme to cleave intracellular domain of notch
- domain translocates to nucleus where it binds and activates transcription factors
intracellular domain
vehicle for signal transduction
Wnt pathway
Wnt proteins (ligand) is family of secreted growth factors involved in cell fate pathways
- bind to receptors Frizzled and LRP
- Wnt, Frizzled andLRP recruit Dishevelled disrupting the destruction complex of proteins
- this prevents phosphorylation go transcription factor B-Catenin
- once unphosphorylated, is stabilized and can translocate to nucleus
- bind to a repressor and form a complex to activate gene transcription
crosstalk
interaction of one signalling pathway with another
final impact on cell/organism depends on..
signal pathways intersecting/ crosstalk
