Topic 11: Cell Signalling Flashcards
1
Q
4 Steps to Cell Signalling
A
- signalling molecules are released (ligands)
- recognition of the signalling molecule by target cell (receptors)
- signal transduction
- Final impact on target cell and subsequent impact on organism as a whole
2
Q
Signal Transduction
A
- the conversion of the extracellular signal into intracellular instructions
3
Q
Modes of communication
A
- direct interaction of a cell with its neighbour
- action of diffusible signalling molecules overs a distance
- some carry signals long distances, others act locally
- cell communication and signal transduction increases in complexity with multicellular organisms
- cell to cell
- paracrine
- autocrine
- endocrine
4
Q
5 Classes of Ligands (signalling molecules)
A
- Steroid hormones
- Eicosanoids
- Neurotransmitters
- Peptide hormones and polypeptide growth factors
- Simple gases
5
Q
Steroid Hormones
A
- small hydrophobic molecule (derived from lipid cholesterol)
- diffuses across cell membrane
- endocrine, paracrine, autocrine modes of action
- bind to intracellular receptors (Nuclear Receptor Superfamily)
6
Q
Eicosanoids
A
- Prostaglandins
- hydrophobic (synthesized from lipids) and are rapidly broken down
- paracrine or autocrine modes of action
7
Q
Neurotransmitters
A
- acetylcholine, dopamine
- hydrophilic molecules that don’t cross the cell membrane
- endocrine, paracrine, autocrine
- bind to cell surface receptors
8
Q
Peptide Hormones and Polypeptide Growth Factors
A
- insulin, epidermal growth fact
- largest and most variable class
- primarily hydrophilic and can’t cross the cell membrane
- endocrine, paracrine, autocrine modes of action
- bind to Cell Surface Receptors
9
Q
Simple Gases
A
- nitric oxide and carbon monoxide
- can move across the cell membrane (passive)
- paracrine mode of action
- bind directly to enzymes, do not use receptors
10
Q
2 Classes of Receptors
A
- Intracellular Receptors
- Nuclear Receptor Superfamily - Cell Surface Receptors
- G-protein coupled receptors
- receptor protein tyrosine kinases
- cytokine receptor superfamily
11
Q
Nuclear Receptor Superfamily
A
- molecules bind these receptors include steroid hormones and thyroid hormones (small, hydrophobic)
- receptors are intracellular proteins (not associated with the membrane)
- these receptors + ligand = transcription factors
- receptors contain both a ligand binding domain and a DNA binding domain
12
Q
Glucocorticoid Action
A
- inactive when bound to a chaperone
- become active when bound to a ligance
- 2 active receptors form a dimer
- dimer translocates to the nucleus
- dimer associates with the co-activator protein HAT
- hormone complex binds to a specific DNA binding site and activates gene transcription
- GLUCOCORTICOID RECEPTOR + LIGAND + HAT COACTIVATOR = ACTIVE GENE TRANSCRIPTION
- nuclear receptors transduce signal from ligand to DNA
- final effect: increase in transcription of a specific gene
13
Q
Gene Regulation by Thyroid Hormone Receptor
A
- thyroid hormone receptor (dimer) is bound to DNA either with or without ligand
- without ligand: receptor binds to corepressor HDAC to repress gene transcription
- hormone present: binds receptor, changing conformation to disassociate from HDAC and associate with HAT allowing gene transcription
14
Q
HDAC
A
- co-repressor
15
Q
HAT
A
- co-activator
16
Q
G-Protein Coupled Receptors
A
- largest family of cell surface receptors
- can bind a variety of ligands
- signals are transmitted to intracellular targets via an intermediary protein (Gprotein)
- contains 3 subunits: alpha, beta, gamma
- transmembrane proteins typically with multiple transmembrane domains
17
Q
Activation of G Protein
A
- extracellular receptor domain binds the ligand
- causes conformational change allowing cytosolic domain to activate a G protein
- alpha subunit dissociate from and carries signal to intracellular target (adenylyl cyclase)
18
Q
Tyrosine Kinase Receptors
A
- CSR linked to intracellular enzymes
- have one transmembrane domain
- enzyme activity by part of intracellular domain of receptor OR separate protein associated with intracellular domain
- receptors dimerize when bound to ligand
19
Q
Tyrosine Kinase Receptors Activation
A
- activate receptors by phosphorylating tyrosine residues on both the receptor and target substrates
- phosphorylated can then associate with downstream targets thereby initiating a signalling cascade
- proteins such as insulin and multiple growth factors recognize these receptors
20
Q
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
A
- ligand binds receptor causing dimerization followed by cross phosphorylation of both receptor dimers
- receptors can associate with downstream signalling molecules which begins a signalling cascade
21
Q
Activation of Nonreceptor Tyrosine Kinase
A
- nonreceptor tyrosine kinases are associated with receptors that contain no catalytic activity (cytokine receptors)
- ligand binding induces dimerization and active tyrosine kinases to autophosphorylate themselves and receptor
22
Q
Intracellular Signal Transduction
A
- chain of reactions that transmit chemical signals from cell surface to intracellular targets (signalling cascade)
- frequently, transcription factors are the final targets of signal cascade
23
Q
Signal Transduction from Nuclear Receptors
A
- Glucocorticoid Action
24
Q
Cyclic AMP
A
- a second messenger associated with G protein coupled receptors
- adenosine monophosphate chemical structure has been modified into cyclic structure
- a phosphate group is covalently bound to both 3’ and 5’ carbon by adenylyl cyclase
- important for response of cells to a variety of hormones
25
Q
Second Messenger
A
- a compound modified as a result of a ligand-receptor interaction
- function to relay the message from the receptor to target
- can be used in multiple pathways
26
Q
Adenylyl Cyclase
A
- an enzyme that catalyzes the formation of cyclic AMP from ATP
- activated by an activated G protein alpha subunit
27
Q
cAMP Phosphodiesterase
A
- an enzyme that degrade cyclic AMP
28
Q
Protein Kinase A (PKA)
A
- a cAMP dependent protein kinase
29
Q
Signal Transduction Initiated through PKA
A
- 2nd messenger cAMP initiates intracellular transduction (chain of reactions or a signalling cascade)
- cAMP binds to PKA
- causes dissociation of PKA regulatory subunits
- PKA phosphorylates downstream target proteins
30
Q
cAMP Inducible Gene Expression
A
- cAMP binds PKA
- subunits of PKA dissociate
- PKA activates transcription factor CREB by phosphorylation
- CREB recruits co-activators and initiates transcription of genes at CRE binding sites
31
Q
CRE
A
- a specific DNA binding element that is in the promotor region of cAMP responsive genes
32
Q
Regulation of Glycogen Metabolism by PKA
A
- PKA phosphorylates two key downstream target enzymes
- activates phosphorylase kinase
- inhibits glycogen synthase
33
Q
cAMP Signalling Pathways
A
- can effect both transcription factors and metabolic enzymes
34
Q
Regulation of Protein Phosphorylation
A
- protein kinases (PKA) don’t function in isolation within the cell
- protein phosphatase (PP1) activity counterbalances PKA activity to fine tune this signalling mechanism
35
Q
Amplification of Signal Transduction
A
- a single receptor can activate multiple G proteins
- -> stimulates adenylyl cyclase to make cAMP which activates PKA - PKA can then phosphorylate multiple targets
- End Result: 1 hormone molecule binding 1 receptor can activate a large # of target proteins
36
Q
MAP Kinase Pathways
A
- cell surface receptors linked to enzymes to produce intracellular signals
- Mitogen-Activated Protein
- multiple different MAP kinase pathways
- these transduction pathways can be associated with both receptor and non-receptor tyrosine kinases
- “cascade of kinases”
- activated in response to a variety of growth factors and other signalling molecules
- Ras-Raf-MEK-ERK (stereotypical MAP kinase pathway)
37
Q
Raf
A
- Rapidly Accelerating Fibrosarcoma
- a protein-serine/threonine kinsase
- activated by Ras
- leads to activation of ERK MAP kinase
38
Q
ERK
A
- Extracellular signal-Regulated Kinase
39
Q
MEK
A
- Map kinase /ERK kinase
- a dual-specificity protein kinase
- activates members of the ERK family by phosphorylation of both threonine and tyrosine residues separated by 1 amino acid
40
Q
Ras Proteins
A
- RAt Sarcoma
- guanine nucleotide-binding proteins that function analogously to the alpha subunits of G proteins
- alternate between inactive GDP-bound and active GTP-bound forms
- integral membrane lipoprotein
- one of the first oncogenes identified in human cancers
- could be directly links to growth factor induced cell proliferation
41
Q
Regulation of Ras Proteins
A
- converted to active GTP-bound state by exchange of GTP for bound GDP, which is stimulated by GEFs
- Was activity is terminated by GTP hydrolysis, which is stimulated by GAPs
42
Q
GEF
A
- Guanine Exchanger Factor
- activates Ras
- in its mutated form oncogenic Ras is “locked” in its GTP binding form
43
Q
GAP
A
- Guanine Activating Protein
- terminates Ras activity
44
Q
Ras Activation Downstream of Receptor Protein-Tyrosine Kinases
A
- intermediate protein links phosphorylated region of tyrosine kinase with other target molecules
- inities the signalling cascade
- many types of these molecules
45
Q
Activation of Raf Kinase
A
- initiates a protein kinase cascade
- Raf phosphorylates MEK
- MEK phosphorylates ERK
- ERK phosphorylates other targets
- -> ERK targets include other protein kinases and transcription factors
46
Q
Mammalian and Yeast cells MAP Kinase Pathways
A
- have multiple MAP K Pathways
- all contain a cascade of 3 kinases
- these pathways are important for the regulation of cell proliferation, differentiation, cell survival
47
Q
Notch Signalling
A
- cell to cell mode of signalling
- Notch receptor (in p. membrane) receives signal from Delta Ligand (m. protein) on surface of an adjacent cell
- Ligand receptor binding activates γ-secretase enzyme to cleave intracellular domain of Notch
- Notch intracellular domain translocates to the nucleus where it binds and activates transcription factors
- intracellular domain is the vehicle for signal transduction
48
Q
Wnt Pathway
A
- disruption of “destruction” complex prevents phosphorylation of the transcription factor β- Catenin
- Unphosphorylatedβ- Catenin is stabilized and can translocate to the nucleus to activate gene transcription (transduction)
- binds to a repressor protein and forms a complex that activates transcription
49
Q
Feedback Loops
A
- regulates the activation of individual pathways
- -> control the extent and duration of signalling activity
- similar in principle to feedback regulation of metabolic pathways
- -> control the activity of signalling pathways
50
Q
Signalling Networks
A
- signalling pathways don’t operate in isolation
- frequent crosstalk bwtn diff. pathways so intracellular signal transduction needs to be understood as an integrated network of connected pathways
- Final impact on cell: multicellular organism depends on signalling pathways intersecting
51
Q
Crosstalk
A
interaction of one signalling pathway with another
52
Q
Elements of Signalling Networks
A
- Negative Feedback
- Positive Feedback
- Feedforward Relay
- Stimulatory Crosstalk
- Inhibitory Crosstalk
53
Q
Signal Transduction Pathways
A
- interact to give us the final impact on a target cell
- involve multiple complex interconnected networks formed by the interactions of multiple signalling pathways within a cell
