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5 extracellular signalling Flashcards

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1
Q

What are the five types of extracellular signalling?

A

Endocrine, Neuronal, Paracrine, Autocrine, Contact-Dependent

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2
Q

How does endocrine signalling work?

A

Hormones travel through the bloodstream to act on distant target cells

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3
Q

What is neuronal signalling?

A

Neurotransmitters are released across synapses to communicate between neurons.

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4
Q

How does paracrine signalling function?

A

Local mediators act on nearby target cells.

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5
Q

What is autocrine signalling?

A

A cell releases signals that act on itself (e.g. growth factors).

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6
Q

How does contact-dependent signalling work?

A

A signalling cell directly contacts the target cell via membrane-bound molecules (e.g. Notch signalling).

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7
Q

What are mitogenic signalling molecules?

A

Growth factors (GFs) that stimulate cell division.

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8
Q

How do growth factors interact with cells?

A

They bind to cell surface receptors to regulate functions like migration, replication, and survival.

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9
Q

What is the role of Fibroblast Growth Factor (FGF) in cancer?

A

FGF8 and FGF17 are overexpressed in prostate cancer.

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10
Q

What is angiogenesis, and how does VEGF contribute to it?

A

Angiogenesis is the formation of new blood vessels, driven by VEGF in tumour cells to meet oxygen demands.

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11
Q

How does FGF1 affect colorectal cancer?

A

Higher FGF1 expression correlates with reduced survival; decreasing FGF1 downregulates tumour growth.

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12
Q

What do growth factor receptors do?

A

They receive extracellular signals and initiate intracellular signalling cascades.

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13
Q

What are receptor tyrosine kinases (RTKs)?

A

RTKs are receptors that transmit GF signals via phosphorylation cascades.

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14
Q

What are the main structural components of RTKs?

A

Growth Factor Binding Site, Transmembrane Domain, Catalytic Region, Target Tyrosine Residues, Extracellular Domain, Intracellular Domain.

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15
Q

What are the four steps in RTK activation?

A

Ligand binding, receptor dimerisation, kinase domain activation, transphosphorylation of tyrosine residues.

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16
Q

What is the role of phospho-tyrosines in RTK signalling?

A

They recruit adaptor proteins that initiate downstream cascades.

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17
Q

What are SH2 domains?

A

Protein modules that bind to phospho-tyrosine residues.

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18
Q

What is Ras, and what does it do?

A

A small GTPase that regulates MAPK signalling.

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19
Q

What are the three isoforms of Ras?

A

H-Ras, N-Ras, and K-Ras.

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20
Q

What happens when Ras is GTP-bound?

A

It activates Raf, initiating the MAPK phosphorylation cascade.

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21
Q

What is the archetypal MAPK pathway?

A

Ras-GTP → Raf → MEK → ERK

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22
Q

What are the five conventional MAPK pathways?

A

ERK, JNK, p38, ERK3/4, ERK5.

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23
Q

What stimuli activate ERK, JNK, and p38 pathways?

A

ERK: Growth factors; JNK: Stress stimuli; p38: Stress, TGF-β, cytokines.

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24
Q

What are key ERK1/2 substrates?

A

Elk-1, c-Myc, c-Fos, c-Jun.

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25
How does Raf activate MEK?
By phosphorylating it on two serine residues (S218/S222).
26
How does MEK activate ERK?
By phosphorylating it on threonine and tyrosine residues.
27
What role do ERK1/2 play in apoptosis?
They phosphorylate pro-apoptotic proteins (BMF, BIM, BIK) to degrade them.
28
What percentage of oncogenes encode tyrosine kinases?
~70%.
29
What are key oncogenes in the MAPK pathway?
Ras, c-Myc, c-Fos, c-Jun.
30
How do RTKs normally get downregulated?
Through clathrin-mediated endocytosis and degradation/recycling
31
What is HIP1, and why is it upregulated in cancer?
A protein involved in RTK recycling that is overexpressed in colon and prostate cancers.
32
What are Sprouty 2 and Kekkon 1?
Negative regulators of RTK signalling.
33
What happens when Sprouty 2 levels decrease?
Increased Ras activation and tumour progression.
34
How does phosphorylation-dependent feedback regulate ERK?
Phosphorylation of EGFR and Raf reduces their activity.
35
What is Trastuzumab (Herceptin)?
A HER2-targeting antibody therapy for breast cancer.
36
How does Trastuzumab inhibit HER2?
Prevents ligand binding, dimerisation, and promotes antibody-dependent cytotoxicity (ADCC).
37
How does Trastuzumab impact ERK signalling?
Reduces ERK1/2 phosphorylation and tumour growth.
38
What is Erdafitinib (Balversa)?
An FGFR inhibitor used in cancer therapy.
39
What does Erdafitinib target?
The ATP-binding pocket of FGFRs.
40
How does Erdafitinib affect cancer cells?
Reduces FGFR phosphorylation and downstream ERK activation.
41
Why is resistance to FGFR inhibitors a concern?
Cancer cells can re-activate RTK signalling via alternative pathways.
42
What is the IC50 value?
The concentration required to inhibit enzyme activity by 50%.
43
How do RTK inhibitors initially impact cancer cells?
They reduce MAPK signalling but can lose effectiveness over time.
44
What is ADCC?
Antibody-dependent cellular cytotoxicity, a mechanism used by immune cells to kill antibody-tagged cancer cells.
45
Why is HER2 overexpression problematic?
It leads to excessive RTK signalling and uncontrolled cell proliferation.
46
What is the significance of KRAS mutations in cancer?
They cause hyperactive Ras-ERK signalling, leading to tumour growth.
47
What cancers have high KRAS mutation rates?
Colon (45%), Pancreas (90%), NSCLC (35%)
48
How do negative feedback mechanisms affect RTK inhibitors?
Loss of feedback inhibition can restore ERK1/2 signalling.
49
What are early response genes in MAPK signalling?
c-Fos, c-Jun, c-Myc.
50
What are late response genes in MAPK signalling?
Cyclins and cyclin-dependent kinases (CDKs).
51
How does ERK1/2 phosphorylation provide negative feedback on the MAPK pathway?
ERK1/2 phosphorylates multiple targets to reduce signalling: EGFR: Phosphorylation at T669 blocks RTK activity. Raf: Phosphorylation at S29, S289, S296, S301, S642 reduces Ras-Raf binding. Sprouty & Kekkon: ERK activation leads to their expression, which represses RTK signalling. DUSP Phosphatases: ERK1/2 upregulates dual-specificity phosphatases (DUSPs) that dephosphorylate MAPKs, inhibiting the pathway.
52
What role do DUSP phosphatases play in MAPK regulation?
DUSP (Dual-Specificity Phosphatases) dephosphorylate ERK1/2, reducing its activation and controlling signal duration.
53
How does Sprouty 2 (Spry2) inhibit RTK signalling?
Spry2 indirectly inhibits Ras activation by interfering with adaptor proteins like Grb2, preventing Ras-GTP loading.
54
How does Kekkon 1 (Kek1) block RTK signalling?
Kek1 directly binds RTKs and prevents GF binding and dimerisation, acting as a competitive inhibitor.
55
Why is the loss of Spry2 linked to cancer progression?
Decreased Spry2 expression removes a key negative feedback mechanism, leading to uncontrolled MAPK activation and tumour growth.
56
What is the role of CBL in RTK regulation?
CBL is an E3 ubiquitin ligase that tags active RTKs for endocytosis and degradation, preventing excessive signalling.
57
How does endocytosis regulate RTK signalling?
RTKs are internalised into endosomes. Depending on signalling needs, they are either: Recycled back to the plasma membrane (prolongs signalling). Degraded in lysosomes (terminates signalling).
58
How does Rab5 regulate RTK trafficking?
Rab5 is a small GTPase that controls the early steps of endosome formation and RTK sorting, influencing signal duration.
59
What mechanisms drive resistance to Erdafitinib (FGFR inhibitor)?
Compensatory Pathway Activation: Tumours upregulate PI3K-AKT or JAK-STAT to bypass FGFR inhibition. Secondary FGFR Mutations: Some FGFR mutations reduce Erdafitinib binding, making the drug less effective. Increased FGFR Expression: Cells may increase FGFR levels to outcompete the inhibitor.
60
How do cancer cells develop resistance to Trastuzumab (Herceptin)?
HER2 Mutations: Some tumours develop mutations in HER2 that prevent Trastuzumab from binding. Compensatory RTK Activation: Other RTKs (EGFR, IGF-1R) can reactivate MAPK even when HER2 is blocked. Altered HER2 Trafficking: Changes in HER2 endocytosis reduce degradation, prolonging signalling. Loss of ADCC Response: Tumours may downregulate Fc receptors on immune cells, reducing antibody-dependent cytotoxicity.
61
What MEK mutations contribute to cancer?
MEK1/2 mutations (e.g. MEK1 F53L, MEK1 Q56P) increase kinase activity, leading to constitutive ERK activation.
62
How do Raf mutations differ in their effects?
B-Raf V600E: Constitutively active, drives melanoma. C-Raf mutations: Less common, often cooperate with Ras mutations.
63
Why do Ras and Raf mutations lead to therapy resistance?
Ras mutations prevent GTP hydrolysis, locking Ras in the active state. B-Raf mutations bypass upstream signals, making RTK inhibitors ineffective.
64
What is the role of PDGF (Platelet-Derived Growth Factor)?
PDGF activates RTKs to stimulate fibroblast proliferation, wound healing, and tumour stroma formation.
65
How does IGF (Insulin-Like Growth Factor) contribute to cancer?
IGF-1R signalling activates MAPK & PI3K-AKT pathways, promoting growth and survival in cancers like breast and prostate cancer.
66
What are key differences between VEGF and FGF in angiogenesis?
VEGF: Primarily stimulates endothelial cells to form blood vessels. FGF: Stimulates both endothelial & stromal cells, leading to wider tissue remodelling.

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