Lecture 15: Cytokine Signaling

cytokines

family of small secreted proteins

what do cytokines control

growth and differentiation of many types of cells

what is Typically referred to in the context of the immune response

cytokines

Activation of cytokine receptors step 1

Receptors form a homodimer in the absence of ligand, but are still inactive

why are associated JAK kinases poorly active in Activation of cytokine receptors step 1

blocking activation loop, do not contact one another

which kinases are poorly active due to blocking activation loop, do not contact one another

JAK

Activation of cytokine receptors step 2

single ligand binds to both receptor ligand-binding sites, conformational change brings JAK kinases together, activation loops are phosphorylated on tyrosine residues

Activation of cytokine receptors step 3

Active JAK kinases phosphorylate tyrosine residues on the receptor cytosolic domain

what do Activated phosphotyrosines on cytokine receptors act as

docking sites for multiple signal-transducing pathways

what act as docking sites for multiple signal-transducing pathways

Activated phosphotyrosines on cytokine receptors

Erythropoietin

cytokine that triggers formation of red blood cells

in what way does cytokine trigger formation of red blood cells within Erythropoietin

Triggers both growth and differentiation of erythroid progenitors

All blood cells come from hematopoietic stem cells, so what ensures only erythroid progenitors become red blood cells

?

In what conditions would you expect increased erythropoietin

?

In what conditions would you expect decreased erythropoietin

?

what do JAK kinases directly activate

STAT transcription factors

STAT

Signal Transducer and Activator of Transcription

After JAK kinase activation step 1

Inactive monomeric STAT binds to phosphotyrosine on the cytokine receptor, JAK phosphorylates STAT

After JAK kinase activation step 2

Phosphorylated STATs dissociate from receptor

After JAK kinase activation step 3

Phosphorylated STATs homodimerize, revealing a nuclear localization signal

After JAK kinase activation step 4

STAT dimer translocates into nucleus, activates transcription of target genes

ways of Terminating cytokine signal transduction

short-term regulation, long-term regulation

short-term regulation

Phosphotyrosine phosphatase SHP1 binds to phosphotyrosines on activated cytokine receptors and dephosphorylates tyrosine in the JAK activation loop

long-term regulation

STAT activation induces expression of SOCS, SOCS binds to phosphotyrosines on JAK or EpoR and blocks binding of other signaling proteins, targets EpoR and JAK2 for ubiquitinproteasome degradation

SOCS

Suppressor Of Cytokine Signaling

what is NF-κB

transcription factor thought to be the master regulator of the mammalian immune system

p65/p50

NF-κB

what happens during the resting state of Activation of the NF-κB signaling pathway

NF-κB is sequestered and inhibited by I-κBα

what happens Upon activation of the NF-κB signaling pathway

I-κBα is polyK48 ubiquitinated by E3 ubiquitin ligase and degraded

what happens at the end of activation of the NF-κB signaling pathway

Free NF-κB enters the nucleus to activate transcription of target genes

transforming growth factor β pathway

ancient family of multifunctional cytokines that bind to TGF receptors

TGF-β

transforming growth factor β pathway

ways on how Signaling is distinct from classical cytokine signaling

Receptor has serine/threonine kinase activity, Transcription factors called Smad, Generally anti-proliferative

How might inhibiting this pathway contribute to disease

?