Signal Transduction: Single Pass Receptors Flashcards
What are the three types of single-pass receptors?
1) cytokine receptors
2) RTKs = receptor tyrosine kinase receptors
3) TGFβ receptors
In general, how do single-pass receptors work?
Unligated (unbound) receptors exist as inactive monomers
Binding of ligand causes dimerization of receptors, forming active heterodimers
Dimerization activates kinase activity in/associated with the receptor.
- Cytokine Receptors: the kinase is EXTRINSIC to the receptor (a separate protein associated with the receptor)
- RTKs and TGFβ Receptros: the kinase is INTRINSIC to the receptor itself (part of the receptor)
The kinase initiates phosphorylation cascade that —> —> —> phosphorylation of TFs
-phosphorylation of TFs alters transcription/gene expression/protein expression
proteins secreted by infected host cells or cancerous cells which bind neighboring cells and activate antiviral/antibacterial/anticancer responses
Inteferons (IFNs)
Mechanism: bind Cytokine Receptors –> JAK/STAT pathway
protein hormone produced in Anterior Pituitary of pregnant women, stimulates mammary glands to produce milk (lactation)
Prolactin (PRL)
Mechanism: binds PRL Receptor (a Cytokine Receptor) in mammary glands –> JAK/STAT pathway —> —> lacation
protein hormone produced by kidneys, stimulates Erythropoeisis (RBC production) in red bone marrow
Erythropoietin (Epo)
Mechanisms: multiple
1) binds EpoR (a Cytokine Receptor) on erythroid progenitor cells –> JAK/STAT pathway –> –> erythroid progenitors differentiate into Erythrocytes (RBC’s)
2) MAPK pathway
3) PLC pathway
erythroid progenitor cells that do NOT bind Epo undergo apoptosis
Describe the mechanism of Cytokine Receptor signaling
JAK/STAT pathway
1) cytokine ligand binds receptor monmers
2) ligation causes dimerization of receptors to form heterodimers; dimerization brings together JAK from different receptors, activating it. JAK is the kinase that is associated with (extrinsic to) each Cytokine Receptor
3) activated JAK proteins autophosphorylate, phosphorylating a Tyr residue on their “lip domain”
4) autophosphorylation causes JAK to phosphorylate Tyr resudues on the Cytokine Receptor.
- These phosphoTyr residues serve as docking sites for proteins with SH2 Domains and PTB Domains (PhosphoTyrosine Binding)
- binding of docking proteins leads to recruitment of additional signalling proteins, ultimately leading to
5) STAT (Signal Tranducer and Activator of Transcription = a TF with an SH2 domain and a DNA-binding Domain) binds phosphotyrosine on Cytokine Receptor via SH2 Domain
6) STAT is phosphorylated by JAK. Phosphorylation causes STAT’s activation and release from receptor
7) activated STAT dimerizes with another actived STAT
8) STAT dimers enter nucleus and activate transcription
Describe the mechanism of RTK signaling
Ras/MAP-K pathway
1) ligand binds RTK monmers
2) ligation causes dimerization of receptors to form heterodimers; dimerization activates the intrinsic tyrosine kinase activity RTK
3) RTK autophosphorylates Tyr residue on its “actiation lip”; autophosphorylation activates phosphorylation of other Tyr residues on the RTK
- These phosphoTyr residues serve as docking sites for proteins with SH2 Domains and PTB Domains (PhosphoTyrosine Binding)
4) GRB2 (a docking protein with an SH2 Domain and an SH3 domain) binds phosophoTyr residue thru its SH2 Domain; this recruits SOS
5) SOS (a GEF, Guanine Exchange Factor) binds GRB2’s SH3 domain; binding activates SOS to catalyze GDP-GTP exchange on Ras (Ras is a monomeric G-protein, membrane bound, Ras-GDP in inactive form, Ras-GTP in active form)
6) Ras-GTP phosphorylates and activates Ref (MAP-KKK)
7) Ref (MAP-KKK) phosphorylates and activates MEK (MAK-KK)
8) MEK (MAP-KK) phosphoryaltes and activates ERK (MAP-K)
9) activated ERK dimerizes, is imported into nucleus by Importin, and phosphorylates and activates many TF’s –> alters transcription
Examples of RTKs
Examples of RTK families
- EGFRs/HERs
- PDGFRs
- FGFRs
- VEGFRs
- RET Receptors
- EphRs
- Insulin Receptors (IR)
Biological roles of RTKs
RTKs involved in 1) Proliferation and 2) Metabolism
1) Prolieration/Differentiation
-most RTK’s bind GF’s, therefore mediate/regulate cellular proliferation and differentiation
Therefore mutations in RTKs often promote CANCER
2) Metabolism
- some RTKs involved in metabolism too
ie. Insulin Receptor (IR) is an RTK
Receptors for Epidermal Growth Factor (EGR)
-clinical significance
Human EGF Receptor (HER) - a subfamily of receptor within EGFR family of RTKs
-four HERs: HER1, HER2, HER3, HER4
-many cancers involve constiutitively activating mutations in HERs
Amplification of this RTK gene is implicated in 25% of breast cancers
HER2
HER2 is amplified in mammary epithelial cells in 25% of breast cancers; breast cancer pts with this amplification have worst prognosis than those without it
HER2 mABs is effective in treating HER2(+) breast cancers
Describe the mechanism of TGFβ receptor signaling
TGFβ/Smad signaling
1) TGFβ Receptors are already activated and phosphorylated when they bind TGFβ
2 )TGFβ binds either RIII (which activates and complexes with RII) or RII directly
3) activation of RII recruits RI (a co-receptor) and activates it
4) RI phosphorylates Smad3, a soluble TF; phosphorylation of Smad3 unmasks its NLS
5) complex of 2 Smad3’s and one Smad4 forms and is imported into nucleus by Importin
6) In nucleus Smads alter transcription
Biological roles of TGFβ / TGFβ Receptors
TGFβ is a paracrine signal;TGFβ Receptors found in Fibroblasts and Epithelial cells
Roles of TGFβ signaling
1) causes Fibroblasts and Epithelial cells to secrete ECM proteins and Protease Inhibitors for proteases that degrade these ECM proteins
2) serves as anti-growth signal
- therefore, inactivating mutations of TGFβ/Smad signaling pathway often promotes cancer
Tx of Multiple Sclerosis
steroids - reduces inflammation associated with damaged neurons
IFNs - acts through Cytokine receptor/JAK-STAT pathway to mediate anti-inflammatory signals and inhibits pro-inflammatory signals
