Grb7 Protein Stability Modulated by Pin1 in Association with Cell Cycle Progression

PLoS One. 2016 Sep 22;11(9):e0163617. doi: 10.1371/journal.pone.0163617. eCollection 2016.

Abstract

Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling and functions. The molecular mechanisms underlying the regulation of Grb7 remain unclear. Here, we revealed a novel negative post-translational regulation of Grb7 by the peptidyl-prolyl cis/trans isomerase, Pin1. Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. Indeed, we found that Pin1 exerts its peptidyl-prolyl cis/trans isomerase activity in the modulation of Grb7 protein stability in regulation of cell cycle progression at the G2-M phase. This study illustrates a novel regulatory mechanism in modulating Grb7-mediated signaling, which may take part in pathophysiological consequences.

Grants and funding

This study was supported by a grant from the Ministry of Science and Technology, https://www.most.gov.tw/en/public (MoST-103-2320-B-002-046), to TLS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.