Lecture 9: Jak Stat Signalling

Question 1

4 Jak proteins domain

Answer 1

1. C-terminal domain, tyrosine kinase activity
2. pseudokinase domain, negative regulate kinase activity
3. FERM N-terminal domain for receptor binding
4. SH2 domain

Question 2

4 types of JAKs

Answer 2

Jak 1 ,2 ,3 and TYK2

Question 3

4 STAT protein domains

Answer 3

well conserved SH2 domain, allow recruitment of activated receptor on its phosphotyrosine residue

Coiled-coil domain of STAT3 essential for SH2 receptor binding

C terminal domain, phosphorylation by JAK

DNA binding domain

Question 4

Seven STAT proteins

Answer 4

STAT1, 2, 3, 4, 5A, 5B, 6

expression are ubiquitous

Question 5

JAK STAT activation

Answer 5

1. cytokine binds to monomer
2. binds to a second monomer and receptor dimerization
3. activation of JAK kinases
4. autophosphorylation of JAK
5. phosphorylate receptor
6. recruit STAT through SH2 recognition domain and binds to phosphotyrosine residue of the activated receptor
7. STAT dimers migrate to nucleus and activate transcription

Question 6

SOCS protein 1-8

Answer 6

have SH2 domain, can bind to receptor to prevent STAT binding

JAK inhibition domain called KIR (kinase inhibitory region)

recruit E3 ubiquitin ligase to destroy receptor and STAT protein

SOCS genes are target genes for the STAT transcription factors and allow NEGATIVE FEEDBACK of this signalling pathway

Question 7

PIAS

Answer 7

bind to phosphorylated STAT protein to prevent their dimerization

Question 8

SHP

Answer 8

SH2 domain-containing phosphatases (SHP) can dephosphorylate JAK kinases

Question 9

STAT3 (transcription factor)

Answer 9

involved in cell survival and proliferation

activate BCL-2, cyclin D1, VEGFA, MYC, JUN and FOS

repressor of TP53 gene which codes for p53 protein

Question 10

3 JAK mutations

Answer 10

V617E- at kinase domain of JAK2, leads to constitutive activation of tyrosine kinase activity and receptor hypersensitivity

K539L- myeloproliferative neoplasia and some acute lymphoblastic leukemias and acute megakaryocytic leukemias

activating mutations of JAK1 and 3 in T cell leukemias and JAK 3 mutations in acute megakaryocytic leukemias

Question 11

3 STAT mutations

Answer 11

behave as proto-oncogenes
rarely involved in malignant cancers

constitutive activation of STAT1, 3, 5

AML, Hodgkin disease AML and ALL CML

Question 12

SOCS mutations

Answer 12

behave as tumor suppressors

SOCS1 promoter methylation, gene inactivation found in 60% of AML

SOCS3 promoter methylation found in hepatocarcinomas and squamous cell carcinoma

Question 13

Anti PD1 and PD-L1

Answer 13

IFN-gamma can activate Jak/Stat and activate PD-1/PD-L1

Jak/Stat inhibitors can downregulate PD1 and PD-L1 to block immunosuppressive environment in tumor