| RRC ID |
90128
|
| 著者 |
Wang P, Han X, Ren K, Li E, Bi H, Aydemir I, Sukhanova M, Liu Y, Yang J, Ji P.
|
| タイトル |
PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via degradation of p53.
|
| ジャーナル |
J Clin Invest
|
| Abstract |
The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). The pleckstrin 2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we reveal peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in patients with MPN and in a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2-mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings reveal PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negative regulation of p53, thus providing a target and opportunity for drug repurposing using cyclosporin A to treat MPNs.
|
| 巻・号 |
135(13)
|
| 公開日 |
2025-7-1
|
| DOI |
10.1172/JCI181394
|
| PII |
181394
|
| PMID |
40338661
|
| PMC |
PMC12208539
|
| MeSH |
Animals
Cell Proliferation
Erythropoiesis
Humans
Janus Kinase 2* / genetics
Janus Kinase 2* / metabolism
Mice
Mice, Knockout
Mutation, Missense
Myeloproliferative Disorders* / genetics
Myeloproliferative Disorders* / metabolism
Myeloproliferative Disorders* / pathology
Proteolysis*
STAT5 Transcription Factor* / genetics
STAT5 Transcription Factor* / metabolism
Signal Transduction*
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
