Chapter 4: PARACRINE Mechanisms of Morphogenesis Flashcards
Paracine signalling: when proteins from one cell diffuses across a ___ distance to induce changes in other cells, through the secretion of signalling proteins (ligands) in EXM
SHORT distance.
___ signalling: cells that secrete the paracrine factors also respond to them through their own receptors. The factor released from the cell induces changes on the same cell that releases it
autocrine signalling.
Placental cytotrophoblast cells use ____ signalling. They secrete platelet-derived growth factor, whose receptor is on the cytotrophoblast cell membrane. The rsult is the explosive proliferation of that tissue
autocrine signalling.
morphogen
diffusable molecules that determine the fate of cells via concentration gradients.
Note; dif transcription factors are turned on at different concentrations of the same morphogen.
when morph conc is high, the cells are specified to one cell type. When morph drops to very high, a dif cell fate is specified.
Explain how the same morphogen can induce differentiation into dif cells in amphibian cells
cells in amphibians contain different concentrations of activin: TGFbeta family paracrine factor.
- low [activin] = Xbra gene expression is activated. triggers gene transcription for muscle growth. also produces brachyury to inhibit goosedoid.
high [activin]: INDUCES goosecoid. Causes gene expression that forms dorsal structures.
therefore, different concentrations of the same morphogen produce and inhibit different genes and result in the formation of different cells and tissues.
the paracrine factor often binds as a ____ to its receptor, which starts a cascade of events within the cell that ultimately regulates a response
ligand. The ligand induces a conformational change in the receptor.
In RTKs, ligand/paracrine factors induces ___ activity IN the receptor that allows the receptor to phosphorylate ___ resides on proteins. Binding of a ligand causes RTKS to___
In RTKs, ligand/paracrine factors induces KINASE activity IN the receptor that allows the receptor to phosphorylate TYROSINE resides on proteins.
- the receptor-ligand autophosphorylates itself, activating it to become another kinase for other proteins.
- the active receptor can now catalyze reaction sthat phosphrylate other proteins, and this phosphorylation in turns activates their latent activation. Further down, phosphorylation activates dormant TFs, or a set of cytoskeletal proteins.
Binding of a ligand causes RTKS to dimerize
4 primary paracrine families
1) FGF
2) WNT
3) hedgehog
4) TGFbeta super family. (TGFbeta, BMP, Nodal, VgF1, Activin)
Functions of FGF1, FGF 2, FGF7, FGF8
FGF1: regeneration
FGF2: blood vessel formation
FGF7: keratinocyte growth factor
FGF8: Embryonic development.
FGF paracrine factors activate FGFR’s, which are a type of:
receptor tyrosine kinase.
When FGF binds to FGFR (an RTK), what does it also bind to? Why?
a heparan sulfate proteoglycan, for stability.
Outline the cascade seen when FGF (fibroblast growth factor) binds to FGFR.
*FGFR is a type of RTK.
1) RTK binds to FGF ligand and HSPG for stability
2) RTK(FGFR) homodimerizes
3) RTK dimers autophosphorylate themselves on their tyrosine residues, activating the dimer
4) SOS(adapter protein) recognizes the autophosphorylated RTK dimer, and activates GEF, connecting the dimer to GEF and the rest of the intracellular signalling system.
5) GEF exchanges RAS-GDP for Ras-GTP.
- - in a counter system, Ras-GTP is later de-phosphorylated by GAP to re-form Ras-GDP.
6) Ras-GTP activates RAF kinase.
7) RAF kinase phosphorylates MEK
8) MEK-P phosphorylates ERK
9) ERK-P enters the nucleus and phosphorylates TFs that belong to the Pea3 family.
10) these activated TFs regulate gene expression, resulting in the further cell division and protein synthesis regulation.
- TF activation is stopped when GAP exchanges Ras-GTP for Ras-GDP, so Ras can no longer activate Raf.
Cascade: RTK(dimer)–> GEF –> RasGTP –> RafP –> Mek –> erk –> TF (Pea3) activation –> Gene expressions via transcription.
When does fibroblast growth factors stop signalling for gene transcription via transcription factor activation?
- TF activation is stopped when GAP exchanges Ras-GTP for Ras-GDP, so Ras can no longer activate Raf.
Outline the FGF paracrine factor cascade via the Jak-Stat pathway
1) FGF/prolactin binds to RTK (FGFR), which also has JAK bound it its intracellular side.
2) Ligand binding to RTK-Jak causes dimerization and autophosphorylation.
3) RTK-Jak dimerization activates the receptor. It then phoshphorylates STAT.
4) STAT-P dimerizes
5) STATP Dimer enters nucleus and binds to Casein gene. Activates transcription of casein gene. Facilitates milk production via prolactin production.
What is the stat pathway involved in
1) activation of casein during milk production
2) differentiation of blood cells
3) growth of limbs.
3 types of hedgehog paracrine factors vertebrates have
1) SHH: ensures neurons are derived from ventral portion of neural tube, ensures feathers are positioned properly in chickens, ensures that our little finger is posterior
2) DHH: found in sertoli cells
3) Indian HH: found in gut and cartilage. Important for bone growth.
After being translated in the ER, how do hedgehog proteins get directed to the cell membrane for release as a paracrine factor?
Hedgehog secretion autoproteolytically cleaves its C-terminus sequence to allow it to be directed to the cell membrane.
After the HH paracrine factor autoproteolytically cleaves its C terminus, what modifications occur? Why?
cholesterol and palmitic acid are required for multimeric assembly. Lipid additions are required for concentration-dependent maintenance of HH.
___ (lipid type) on HH interacts with ___ to allow HH to be secreted as a monomer
CHOLESTEROL (lipid type) on HH interacts with DISPATCHED RECEPTER to allow HH to be secreted as a monomer.
HH INTERACTS WITH ___ ____ ___ (HSPG) TO ALLOW FOR AGGREGATION IN ___ STRUCTURES
HH INTERACTS WITH HEPAREN SULPHATE PROTEOGLYCANS (HSPG) TO ALLOW FOR AGGREGATION IN LIPOPROTEIN STRUCTURES
In order for HH to be secreted as a multimer, what is required?
palmitic acid and cholesterol additions on HHs link together to link all HH on the membrane.
4 ways Hedgehog paracrine factor can be secreted from host cell
1) monomer (via cholesterol-dispatched)
2) multimer (via cholesterol-palmitic acid)
3) lipoprotein (via heparin sulphate proteoglycan)
4) exovesicle.
Outline the innate pathway that exists when no HH is present.
If no HH is present, Patched receptor will continue to inhibit Smoothened, resulting in its degradation.
- because there is no Smoothened action, Ci(drosophila)/Gli(humans) remain tethered to the microtubules of the responding cell.
- Ci/Gli is bound to the MTs through Cos2/Kif7, Fused (only in drosophila) and Sufu.
- while Ci/Gli is bound to MT, it gets cleaved by PKA and Slimb (only in Drosophila) complex. A portion of Ci/Gli enter the nucleus. The Ci/Gli portion acts as a TRANSCRIPTIONAL REPRESSOR.
