Dataset Information

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

ABSTRACT: Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study of phosphorylation targeting chimeras (PhosTACs). Similar to PROTACs in their ability to induce ternary complexes, PhosTACs focus on recruiting a Ser/Thr phosphatase to a phosphosubstrate to mediate its dephosphorylation. However, distinct from PROTACs, PhosTACs can uniquely provide target gain-of-function opportunities to manipulate protein activity. In this study, we applied a chemical biology approach to evaluate the feasibility of PhosTACs by recruiting the scaffold and catalytic subunits of the PP2A holoenzyme to protein substrates such as PDCD4 and FOXO3a for targeted protein dephosphorylation. For FOXO3a, this dephosphorylation resulted in the transcriptional activation of a FOXO3a-responsive reporter gene.

SUBMITTER: Chen PH

PROVIDER: S-EPMC10437008 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

Chen Po-Han PH Hu Zhenyi Z An Elvira E Okeke Ifunanya I Zheng Sijin S Luo Xuanmeng X Gong Angela A Jaime-Figueroa Saul S Crews Craig M CM

ACS chemical biology 20211115 12

Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study o ...[more]

PMID: 34780684

Similar Datasets

Project description:BackgroundThe dynamic changes that occur in protein expression after treatment of a cancer in vivo are poorly described. In this study we measure the effect of chemotherapy over time on the expression of a panel of proteins in ovarian cancer xenograft models. The objective was to identify phosphoprotein and other protein changes indicative of pathway activation that might link with drug response.MethodsTwo xenograft models, platinum-responsive OV1002 and platinum-unresponsive HOX424, were used. Treatments were carboplatin and carboplatin-paclitaxel. Expression of 49 proteins over 14 days post treatment was measured by quantitative immunofluorescence and analysed by AQUA.ResultsCarboplatin treatment in the platinum-sensitive OV1002 model triggered up-regulation of cell cycle, mTOR and DDR pathways, while at late time points WNT, invasion, EMT and MAPK pathways were modulated. Estrogen receptor-alpha (ESR1) and ERBB pathways were down-regulated early, within 24 h from treatment administration. Combined carboplatin-paclitaxel treatment triggered a more extensive response in the OV1002 model modulating expression of 23 of 49 proteins. Therefore the cell cycle and DDR pathways showed similar or more pronounced changes than with carboplatin alone. In addition to expression of pS6 and pERK increasing, components of the AKT pathway were modulated with pAKT increasing while its regulator PTEN was down-regulated early. WNT signaling, EMT and invasion markers were modulated at later time points. Additional pathways were also observed with the NFκB and JAK/STAT pathways being up-regulated. ESR1 was down-regulated as was HER4, while further protein members of the ERBB pathway were upregulated late. By contrast, in the carboplatin-unresponsive HOX 424 xenograft, carboplatin only modulated expression of MLH1 while carboplatin-paclitaxel treatment modulated ESR1 and pMET.ConclusionsThirteen proteins were modulated by carboplatin and a more robust set of changes by carboplatin-paclitaxel. Early changes included DDR and cell cycle regulatory proteins associating with tumor volume changes, as expected. Changes in ESR1 and ERBB signaling were also observed. Late changes included components of MAPK signaling, EMT and invasion markers and coincided in time with reversal in tumor volume reduction. These results suggest potential therapeutic roles for inhibitors of such pathways that may prolong chemotherapeutic effects.

Dataset Information

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

Publications

Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets