4.1. Hydrophilic Proliferative Signalling Pathways

Question 1

MAPK signaling pathway

Answer 1

Proliferation

Question 2

PI3K/ AKT pathway

Answer 2

Pro survival

Question 3

Ligands/ 1st messengers

Answer 3

1. Pathway

2. Regulates cellular responses to growth factors

Question 4

EGF

Answer 4

1. Epidermal growth factor
2. Produced by macrophages, platelets & epithelial cells in various organs including kidney, salivary gland and stomach

Question 5

PDF

Answer 5

1. Platelet derived growth factor
2. Crucial roles during development
3. Produced by platelets, smooth muscle cells, activated macrophages & endothelial cells amongst others
4. Some secreted in an inactive form & are cleaved by proteases in the ECM & activated

Question 6

FGF

Answer 6

1. Fibroblast growth factor

2. Important in the control of development

Question 7

Heparan sulphate proteoglycans

Answer 7

Important role in cell signaling by binding growth factors such as FGF & PDGF ->
Serves to restrict their action to areas close to their sites of release

Question 8

VEGF

Answer 8

1. Vascular endothelial growth factor

2. Major role angiogenesis

Question 9

Angiopoeitins

Answer 9

1. Primary functions = control angiogenesis

2. Important in cell adhesion of haematopoietic stem cells (HSCs) to the stem cell niche

Question 10

MAPK

Answer 10

Mitogen activated protein

Question 11

PI3K

Answer 11

Phosphoinositide-3-kinase

Question 12

GEF

Answer 12

Guanine nucleotide exchange factor

-> binds to adaptor protein domain & exchanges GDP on inactive RAS for GTP & activates RAS

Question 13

MAPK Pathway

Answer 13

1. Phosphorylation tyrosine amino acids in tail of receptor bind adaptor proteins
2. These bind GEFs that donates a GTP to a small monomeric G-protein, RAS & activates it
3. This activates the MAPK phosphorylation cascade => phosphorylation of enzymes, other kinases & transcription factors
4. Cascade leads to altered transcription of genes that are important for the cell cycle & hence proliferation
5. This pathway plays an important role in proliferation & many proteins within it are proto-oncogenes

Question 14

Receptor tyrosine kinase signaling:

PI3K

Answer 14

1. Phosphoinsitide 3 kinase (PI3K) is recruited to the phosphorylated receptor & its SH2 domain binds
2. PI3K phosphorylates a phospholipid (PIP2) in the membrane to produce the second messenger phosphoinositide triphosphate (PIP3)
3. This turn recruits AKT kinase to the membrane by binding to its PH domain
4. AKT is activated & subsequent phosphorylates proteins involved in survival & proliferation

Question 15

Wnt pathway

Answer 15

1. Plays important role in embryogenesis & in the proliferation of colorectal epithelial
2. Important in bone formation & remodeling in human joint diseases such as rheumatoid arthritis (inhibited pathway) & ankylosing spondylitis (overactive pathway)
3. Modulation of this pathway by gene therapy to treat arthritis & various cancers is currently under investigation

Question 16

Wnt pathway:

No ligand

Answer 16

1. When no ligand is present, the degradation complex forms consisting of glycogen synthase kinase, APC, Axin & beta catenin
2. Within the degradation complex in the cytoplasm, glycogen synthase kinase (GSK) phosphorylates beta catenin
3. Results in its recognition by ubiquitin ligases, ubiquitination & subsequent degradation by the proteasome
4. No gene expression occurs

Question 17

Wnt pathway:

Ligand present

Answer 17

1. Wnt ligand binds to receptor frizzled & LRP
2. LRP binds axin & GSK is inhibited
3. Degradation complex doesn’t form & beta catenin is not phosphorylated & degraded
4. Beta catenin is then able to accumulate, move to the nucleus, bind to TCF & initiate transcription of genes required for proliferation