Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.10.2 (
focal adhesion kinase
)
44,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of myeloid cells. Most MPN patients have a point mutation in
JAK2
(
JAK2
V617F
), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In
Drosophila
, this pathway is simplified, with a single JAK, Hopscotch (Hop), and a single STAT transcription factor, Stat92E. The
hop
Tumorous-lethal
[
hop
Tum
] allele encodes a dominant-active kinase that induces sustained Stat92E activation. Like MPN patients,
hop
Tum
mutants have significantly more myeloid cells, which form invasive tumors. Through an unbiased genetic screen, we found that heterozygosity for
Enhancer of Polycomb
[
E(Pc)
], a component of the Tip60
lysine acetyltransferase
complex (also known as KAT5 in humans), significantly increased tumor burden in
hop
Tum
animals. Hematopoietic depletion of
E(Pc)
or other Tip60 components in an otherwise wild-type background also induced blood cell tumors. The
E(Pc)
tumor phenotype was dependent on JAK/STAT activity, as concomitant depletion of
hop
or
Stat92E
inhibited tumor formation. Stat92E target genes were significantly upregulated in
E(Pc)-
mutant myeloid cells, indicating that loss of
E(Pc)
activates JAK/STAT signaling. Neither the
hop
nor
Stat92E
gene was upregulated upon hematopoietic
E(Pc)
depletion, suggesting that the regulation of the JAK/STAT pathway by E(Pc) is dependent on substrates other than histones. Indeed,
E(Pc)
depletion significantly increased expression of Hop protein in myeloid cells. This study indicates that E(Pc) works as a tumor suppressor by attenuating Hop protein expression and ultimately JAK/STAT signaling. Since loss-of-function mutations in the human homologs of E(Pc) and Tip60 are frequently observed in cancer, our work could lead to new treatments for MPN patients.This article has an associated First Person interview with the first author of the paper.
...
PMID:Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity. 3107 79
