Negative Regulators Flashcards
Using an annotated diagram, describe the activation & downregulatory mechanisms associated with the insulin receptor. How is specificity maintained in the recruitment of downstream signalling molecules (full description of downstream signalling pathways is not needed)?
Activation of insulin receptor (1) (1/3)
- Insulin binds to IR = autophosphorylation (ligand binding induces a CC, activates the intrinsic kinase activity of the receptor chains)
- Tyr phos of insulin receptor substrate (IRS) proteins & other signalling molecules (Shc)
- p-IRS = docking proteins for other signalling proteins (PI3K, Grb2)
- PI3K binding to pY on IRS-1 induces PI3K activation → initiation of downstream cascade → phos & activation of Akt & PKC (gluc transport & syn of lipids, proteins & glycogen)
- Grb2 activation = dep on activation of SHC but can be (in)dependent of IRS-1 → Activation of MAPL signalling pathways → prolif & growth
BASIC ORDER:
- IR @ plasma membrane, Ins binds extracellularly
- IR autophosphorylation created binding sites for IRS and SHC
1) SHC
- SHC = docking platform for Grb2:SOS:RAS complex that uses GTP to activate the Raf-1/MEK/Erk1/2 cascade resulting in cell proliferation & growth
2) IRS
- IRS = docking platform for Grb2 and SOS which can then move to SHC to promote the formation of SHC:Grb2:SOS:RAS complex which activates the Raf-1 downstream cascade (so Grb2 activation can be (in)dependent of IRS)
- alternatively IRS can activate PI3K
- PI3K can activate PKC to increase glucose uptake
- PI3K can activate Akt to increase syn of lipids, proteins & glycogen, as well as increase glucose uptake
Using an annotated diagram, describe the activation & downregulatory mechanisms associated with the insulin receptor. How is specificity maintained in the recruitment of downstream signalling molecules (full description of downstream signalling pathways is not needed)?
Downregulatory mechanisms of insulin receptor (1) (2/3)
- IR is an RTK
- Receptor chains have Tyr residues wh/ can be phos when ins binds
- Deactivation of this pathway (glucose & lipid metabolism) is dependent on PTP1B
- PTP1B = on ER-memb
- when IR = stimulated, translocates & dephos the pY on the IR and on IRS
- switches the pathway off
Using an annotated diagram, describe the activation & downregulatory mechanisms associated with the insulin receptor. How is specificity maintained in the recruitment of downstream signalling molecules (full description of downstream signalling pathways is not needed)?
How is specificity maintained (1) (3/3)
- signalling molecules = made up of different SU
- bringing them together ensures specificity of the resp
- mix & match SU of negative reg, reduces genes needed
Negative regulators
- Scaffolding SU - allows molecules to interact w/ receptor signalling complexes
- Regulatory SU - det whether regulator is active
- Catalytic SU - carry out dephos
- PID will only bind app motifs: pY → SH2. PTB
Example of a dysregulated negative regulator
Ceramide in the general pathophysiology of Type 1/2 diabetes (Ceramide; roles; β-cell apoptosis mechanisms; insulin signalling IMD) (2) (1/2)
- when IR signalling = wrong, diseases may manifest i.e., diabetes
- Ceramide = prime sphingolipid signalling molecule
- has been implicated in T1/2D
- have used cultured cells, animal models & human subjects to demonstrate the role of ceramide in T1/2D
- roles in β-cell apoptosis, Ins resistance, & ↓ of ins gene XPS’ion
- β-cell apoptosis can be induced by ceramide in multiple ways:
- activation of extrinsic apoptotic pathway
- induction of ER-stress
- inhibition of Akt
- Ceramide can modulate ins sig IMD:
- IRS, Akt, GLUT-4
Example of a dysregulated negative regulator
Ceramide in β-cell apoptosis (cytokine; biosynthesis of ceramide; ceramide activity, mito, ER, gene XPS’ion) (2) (2/2)
- ceramides role in β-cell apoptosis may be induced by cytokines
- cellular ceramide formed by de novo biosynthesis from precursor, palmitate, and activation of extrinsic pathway of apoptosis by FasL or TNFα binding to the FAS-R and TNF-R
- ceramide acts on mito & causes release of ROS/RNS & cytochrome C - activates intrinsic apoptotic pathway
- ↑ ROS further increases ceramide prod
- ceramide can act on ER & cause ER stress-mediated apoptosis
- ceramide inhibits ins gene XPS’ion
Compare & contrast the composition & activation mechanisms of growth factor & cytokine receptors. Give an example of how the dysregulation of each can cause disease.
Receptor chains (3) (1/5)
GFR
- homodimer
CR
- heterodimer
- 1x ligand specific chain
- 1x common signalling chain
Compare & contrast the composition & activation mechanisms of growth factor & cytokine receptors. Give an example of how the dysregulation of each can cause disease.
Ligand (3) (2/5)
GFR
- 2 molecules
CR
- 1 molecule
Compare & contrast the composition & activation mechanisms of growth factor & cytokine receptors. Give an example of how the dysregulation of each can cause disease.
Activation (3) (3/5)
GFR
- intrinsic kinase domain
- activates & phos receptor
CR
- Associated JAK kinases
- activates & phos receptor
Compare & contrast the composition & activation mechanisms of growth factor & cytokine receptors. Give an example of how the dysregulation of each can cause disease.
Signalling molecule recruitment (3) (4/5)
GFR
- Grb2 directly
CR
- Adaptor proteins link to Grb2
Compare & contrast the composition & activation mechanisms of growth factor & cytokine receptors. Give an example of how the dysregulation of each can cause disease.
Changes in disease (3) (5/5)
GFR
- Over-XPS’ion or constitutive activation
- cancer
CR
- Loss of XPS’ion due to loss of common chain usually
- immunodeficiency i.e., SCID (severe combined immunodeficiency)
