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cytokines

• cytokines are small secreted proteins that by binding to transmembrane receptors regulate cell-            
• - survival, proliferation, differentiation, activation
• cytokines play especially key roles in immune, hematopoietic and neuronal cell lineages

receptor families

• cytokines signal throgh transmembrane receptors that can be grouped according to their extracellular and cytoplasmic domains

1. tyrosine kinase receptors
2. serine threonine kinase receptor
3. class-1 cytokine receptors
4. class2 cytokine receptors
5. tumour necrosis factor-related
6. immunoglobulin superfamily (non-RTK)
7. G-protien coupled receptors

• examples: 

1. leptin
2. growth hormone
3. prolactin
4. erythropoeitin
5. thrombopoietin
6. GCSF
7. IL-3,5
8. GMCSF

4-helix bundle cytokines

• all class 1 and 2 cytokine receptors bind ligands that have a common four-alpha helical strucutre

receptor features

cytokine class 1 receptor

• extracellular- WSXWS motif, 4 conserved cysteine residues
• intracellular - NO INTRINSIC KINASE ACTIVITY, conserved membrane-proximal alpha-helical segment that binds JAKs

cytokine class 2 receptors

• extracellular- 4 conserved cystienes
• intracellular - as above

JAK-stat pathways

• JAK : cytoplasmic tryosine kinase 
• activate kinase and pseudo kinase domain
• receptor binding domain

1. cytokine receptors without ligand binding
2. dimerization and phosphorylation of activation lip tyrosines
3. phosphorylation of additional tyrosine residues
4. into nucleus; binds DNA and activates transcription

• short term regulation : JAK2 deactivationn by SHP1 phosphate
• long term regulation: signal blocking and protein degradation by SOCS proteins

specifity in thein thte JAK-STAT pathway

• hundreds of cytokines
• >50 class 1 and 2 REceptors
• 4 family me,bers : JAK, JAK2/3, TYK2
• 7 family memebers : STAT1, 2, 3, 4, 5a, 5b, 6
• the amino acid sequences of the rece[ptor cytoplasmic domains determine the H=JAK/STAT pairing

STAT : signal transducer and activator of transcription

• transcriptional activation domain
• protein-protein interaction domains
• DNA binding Domain ( bind to cytokine-receptors
• SH2 domain/dimerization domain
• c-terminal tryosine

additional pathways

• STATs are not the only protein that bimds phosphorylated tyrosines on…