NF-kB

The NF-  B/Rel family ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The NF-  B/Rel family ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Signal transduction pathway Cytoplasm inactive Nucleus active Signals

Common DBD: Rel-homology domain (RHD) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Spec.DNA-binding dimerization IkB-interaction NLS

Homo- and heterodimers ,[object Object],[object Object],[object Object]

Two main classes of RHDs ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Two main classes of RHDs +TAD - TAD p105 p50 p100 p52 RelA(p65) cRel RelB Rel homology domain C-terminal I  B-like domains Acitvation domains

RHD proteins Ankyrin repeats RHD

Dimer-formation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

3D structure - DNA interaction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],N-terminal domain C-terminal domain

Structure: NF  B (p50-p65) + DNA Side view ,[object Object],[object Object],[object Object],[object Object]

3D structure - DNA interaction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

3D structure - protein interaction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The I-  B proteins N-terminal Regulatory domain Ankyrin repeats

The I  B-family ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

NF  B-I  B complex IkB HMG I(Y)

Cytoplasmic retention due to interaction with I  B-family proteins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Several I  B-factors with different properties ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Upstream and downstream Upstream Downstream NF- k B Signal transduction pathways + + . . + . .

Signaling ,[object Object],[object Object]

Multiple signalling pathways activate NF-  B ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

One type of signaling hits I-  B through phosphorylation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],? Kinase?

The I  B-kinase complex central in the pathway I  B-kinase complex

The IKK  -kinase becomes activated through phosphorylation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Ser-OH Ser-OH Ser- P Ser- P Signal Upstream kinase inactive active IKKß I  B inactive P P P P Autophosphorylation

Stimulus-specific signal transduction pathways?

Stimulus-specific signalling pathways? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Alternative IKK-kinases Alternative IKK-complexes Signal 1 Signal 2 Signal 3

Why two kinases? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Ser-OH Ser-OH Ser- P Ser- P Signal upstream kinase inactive active IKKß I  B

The next indication: KO phenotypes of IKK  ≠ IKK  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

A separate signaling pathway through IKK  ,[object Object],[object Object],[object Object],[object Object]

The solution Processing depends on IKK  Target of IKK 

Model - two divergent pathways through the IKK complex TNF-R Altered processing of p100 NIK Signal 2 Affect B-cell maturation A role in adaptive immunity A role in innate immunity

Two kinases - two main signaling pathways ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Families of target genes ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],NF-  B is both being activated by and inducing the expression of inflammatory cytokines NF-  B activation can spread from cell to cell

Negative feedback: Attenuation of respons ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Target genes: Link to cancer ,[object Object],[object Object],[object Object],[object Object],Angiogenesis Metastasis

Viruses exploit NF-  B ,[object Object],[object Object],[object Object]

Constitutively nuclear NF-  B ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Link: inflammation - cancer ,[object Object],[object Object],[object Object],[object Object]

Mechanisms of NF-  B activation promoting leukemia ,[object Object],[object Object],[object Object],[object Object],[object Object],1. 2. 3. 4. Tumour cells in which NF-  B is constitutively active are highly resistant to anticancer drugs or ionizing radiation.

Breast cancer: Signalling pathways that stimulate proliferation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Blocking the response ,[object Object],[object Object],[object Object],[object Object],[object Object]

Therapeutic inhibition of NF  B ,[object Object],[object Object],[object Object]

NF-kB

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