Reciprocal antagonism of PIN1-APC/C CDH1 governs mitotic protein stability and cell cycle entry.
Shizhong KeFabin DangLin WangJia-Yun ChenMandar T NaikWenxue LiAbhishek ThavamaniNami KimNandita M NaikHuaxiu SuiWei TangChenxi QiuKazuhiro KoikawaFelipe BataliniEmily Stern GatofDaniela Arango IsazaJaymin M PatelXiaodong WangJohn Gerard ClohessyYujing Jan HengGalit LahavYansheng LiuNathanael S GrayXiao Zhen ZhouWenyi WeiGerburg M WulfKun Ping LuPublished in: Nature communications (2024)
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.
Keyphrases
- cell cycle
- cell proliferation
- protein kinase
- protein protein
- amino acid
- binding protein
- gene expression
- dna methylation
- genome wide
- mouse model
- squamous cell carcinoma
- transcription factor
- high throughput
- inflammatory response
- papillary thyroid
- cancer therapy
- squamous cell
- immune response
- cell death
- drug delivery
- signaling pathway
- bone mineral density
- postmenopausal women