Week 5 Modern cancer therapies
SMDs/biologics, targeting RTK signaling in cancer
Main differences between RTKs and GPCRs:
RTK GPCR Cytokine receptors
Domains 1 tyrosine kinase domain Seven transmembrane Ligand-binding domain
integrated intracellularly . domain extracellularly. Intracellularly
Extracellular domains binds with associated tyrosine
differ (single-pass kinase, called JAK (single-pass
membrane protein) membrane protein)
Activates Ras/MAP kinase cascade Enzyme cascades with JAK/STAT pathway
(involves kinase activity) G proteins (involves
GTPase)
Triggers Many cell reponses (e.g. Only one cell response Immune responses and
differentiation and (involved in vision, inflammation
proliferation) smell, taste, and pain)
Example EGFR, insulin receptor Olfactory, rhodopsin Epo
receptors
Tutorial Lecture Receptor Tyrosine Kinases
Basic principle: conformational change will lead to the next step. Conformational changes are
induced by protein binding or phosphorylation regulate activity of enzymes/targets.
Cytokine receptors
- Mostly signaling via JAK (just another kinase). = protein bound to the intracellular domain of
cytokine receptors to give kinase activity. So epo receptor is not a kinase.
- Single-pass membrane protein, conserved structure: 4 alpha helixes
- Cytokine ligands (interferons and growth hormone) induce conformational change -> trans-
autophosphorylation of JAKs -> phosphorylates residues on C-terminal tails -> activates STAT
-> responses (stimulate or repress immune system (control growth/proliferation of specific
cells)
o Erythropoietin (Epo) ligand: induces production of red blood cells (1 epo will bind 2
receptors)
o Interleukins and interferons regulate inflammatory processes
, JAK/STAT signaling pathway
When ligand binds (e.g. Epo), JAK is phosphorylated at the activation lip -> C-terminal tails are
phosphorylated -> SH2 domain of STAT protein binds (STAT = transcription factor itself, not a kinase))
-> JAK phosphorylates STAT -> STAT dimerizes, goes into nucleus and binds to DNA to activate
transcription (NLS exposure).
Cytokine receptors can induce the same pathways and both effect gene transcription
- Cytokine receptors -> JAK/STAT pathway -> effect on gene transcription.
- RTK -> Ras-MAPK cascade -> effect on gene transcription
Receptor tyrosine kinases (RTKs)
- Single-pass membrane proteins (cross membrane once)
- Structural domains in the extracellular region, and contain their own kinase intracellularly
- Function:
o Survival, proliferation and angiogenesis
o Growth factors that stimulate differentiation and proliferation of cells signal via
these kinds of receptors
o Insulin receptor is an RTK: regulated expression of genes that control metabolism
(already a dimer in unbound state, conformational change needed for activation)
o 2 FGF ligands binds 2 FGFRs and links them together and stabilize by heparan sulfate
- If one cell expresses the receptor and the other the ligand you get cell-cell connections
SMDs/biologics, targeting RTK signaling in cancer
Main differences between RTKs and GPCRs:
RTK GPCR Cytokine receptors
Domains 1 tyrosine kinase domain Seven transmembrane Ligand-binding domain
integrated intracellularly . domain extracellularly. Intracellularly
Extracellular domains binds with associated tyrosine
differ (single-pass kinase, called JAK (single-pass
membrane protein) membrane protein)
Activates Ras/MAP kinase cascade Enzyme cascades with JAK/STAT pathway
(involves kinase activity) G proteins (involves
GTPase)
Triggers Many cell reponses (e.g. Only one cell response Immune responses and
differentiation and (involved in vision, inflammation
proliferation) smell, taste, and pain)
Example EGFR, insulin receptor Olfactory, rhodopsin Epo
receptors
Tutorial Lecture Receptor Tyrosine Kinases
Basic principle: conformational change will lead to the next step. Conformational changes are
induced by protein binding or phosphorylation regulate activity of enzymes/targets.
Cytokine receptors
- Mostly signaling via JAK (just another kinase). = protein bound to the intracellular domain of
cytokine receptors to give kinase activity. So epo receptor is not a kinase.
- Single-pass membrane protein, conserved structure: 4 alpha helixes
- Cytokine ligands (interferons and growth hormone) induce conformational change -> trans-
autophosphorylation of JAKs -> phosphorylates residues on C-terminal tails -> activates STAT
-> responses (stimulate or repress immune system (control growth/proliferation of specific
cells)
o Erythropoietin (Epo) ligand: induces production of red blood cells (1 epo will bind 2
receptors)
o Interleukins and interferons regulate inflammatory processes
, JAK/STAT signaling pathway
When ligand binds (e.g. Epo), JAK is phosphorylated at the activation lip -> C-terminal tails are
phosphorylated -> SH2 domain of STAT protein binds (STAT = transcription factor itself, not a kinase))
-> JAK phosphorylates STAT -> STAT dimerizes, goes into nucleus and binds to DNA to activate
transcription (NLS exposure).
Cytokine receptors can induce the same pathways and both effect gene transcription
- Cytokine receptors -> JAK/STAT pathway -> effect on gene transcription.
- RTK -> Ras-MAPK cascade -> effect on gene transcription
Receptor tyrosine kinases (RTKs)
- Single-pass membrane proteins (cross membrane once)
- Structural domains in the extracellular region, and contain their own kinase intracellularly
- Function:
o Survival, proliferation and angiogenesis
o Growth factors that stimulate differentiation and proliferation of cells signal via
these kinds of receptors
o Insulin receptor is an RTK: regulated expression of genes that control metabolism
(already a dimer in unbound state, conformational change needed for activation)
o 2 FGF ligands binds 2 FGFRs and links them together and stabilize by heparan sulfate
- If one cell expresses the receptor and the other the ligand you get cell-cell connections
