Dynamic regulation of Pin1 expression and function during zebrafish development.

Maria Solange Ibarra,Giannino Del Sal,Carla Borini Etichetti,Germán L Rosano,Ezequiel Margarit,Javier Girardini,Carolina Di Benedetto,Marina Mione,Eric A Shelden

doi:10.1371/journal.pone.0175939

Abstract

The prolyl isomerase Pin1 plays a key role in the modulation of proline-directed phosphorylation signaling by inducing local conformational changes in phosphorylated protein substrates. Extensive studies showed different roles for Pin1 in physiological processes and pathological conditions such as cancer and neurodegenerative diseases. However, there are still several unanswered questions regarding its biological role. Notably, despite evidences from cultured cells showing that Pin1 expression and activity may be regulated by different mechanisms, little is known on their relevance in vivo. Using Danio rerio (zebrafish) as a vertebrate model organism we showed that pin1 expression is regulated during embryogenesis to achieve specific mRNA and protein distribution patterns. Moreover, we found different subcellular distribution in particular stages and cell types and we extended the study of Pin1 expression to the adult zebrafish brain. The analysis of Pin1 overexpression showed alterations on zebrafish development and the presence of p53-dependent apoptosis. Collectively, our results suggest that specific mechanisms are operated in different cell types to regulate Pin1 function.

Highlights

Signal transduction mechanisms make use of phosphorylation reactions to achieve rapid and reversible regulation of pathways underlying cell behavior
We found that the percentage of 3 dpf embryos with alterations in head development was significantly reduced in embryos injected with EGFP-WW or EGFP-Pin1C109A mRNAs comparing with embryos overexpressing EGFP-Pin1 mRNA (Pin1), supporting the notion that isomerase activity is involved in the observed effect (Fig 5B)
The dependence on the particular combination of protein substrates present in a specific cell type and on the activation of signaling pathways able to phosphorylate Pin1 binding sites have complicated the rationalization of its function

Summary

Introduction

Signal transduction mechanisms make use of phosphorylation reactions to achieve rapid and reversible regulation of pathways underlying cell behavior. Among Ser/Thr kinases, those that preferentially phosphorylate Ser or Thr residues preceding Pro in protein substrates (S/T-P motifs) are known as proline-directed kinases. This group includes several kinases from the Cyclin-dependent kinase (CDKs), Extracellular signal–Regulated kinase (ERKs), p38, and Jun N-terminal kinase (JNKs) families, as well as Glycogen synthase kinase 3 (GSK3), Polo-Like Kinase 1 (PLK1) and Mechanistic Target of Rapamycin (mTOR) among others [1]. A unique feature of signaling pathways that include prolinedirected phosphorylation is that they may be further regulated by post-phosphorylation conformational changes through isomerization of the peptide bond preceding Pro [2].

Methods

Results

Conclusion