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.

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PurposeThe authors aimed to chronicle the evolution of the medical community's study of physician and surgeon pregnancy by investigating thematic trends in the literature in the context of pertinent sociopolitical events. MethodA scoping review was conducted in Cochrane Library, Google Scholar, Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science Core Collection from inception through August 11, 2020, using vocabulary and terms for physicians (including surgeons), pregnancy, and family leave. Study populations were categorized by all physician specialties or exclusively surgical specialties as well as by all career levels or exclusively trainees.

Highlights d There is an allosteric pathway between the DFG motif and the molecular brake d An isoleucine near the DFG motif serves as a conduit of allostery d Pathological mutations at the molecular brake perturb the allosteric network d Molecular brake mutants decrease kinase thermal stability