Details

Autor(en) / Beteiligte

• Ke, Shizhong
• Dang, Fabin
• Wang, Lin
• Chen, Jia-Yun
• Naik, Mandar T.
• Li, Wenxue
• Thavamani, Abhishek
• Kim, Nami
• Naik, Nandita M.
• Sui, Huaxiu
• Tang, Wei
• Qiu, Chenxi
• Koikawa, Kazuhiro
• Batalini, Felipe
• Stern Gatof, Emily
• Isaza, Daniela Arango
• Patel, Jaymin M.
• Wang, Xiaodong
• Clohessy, John G.
• Heng, Yujing J.
• Lahav, Galit
• Liu, Yansheng
• Gray, Nathanael S.
• Zhou, Xiao Zhen
• Wei, Wenyi
• Wulf, Gerburg M.
• Lu, Kun Ping

Titel

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry

Ist Teil von

• Nature communications, 2024-04, Vol.15 (1), p.3220-3220, Article 3220

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/C CDH1 ) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/C CDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/C CDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/C CDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer. Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/C CDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.