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.
Highlights
Growth factor receptor bound protein 7 (Grb7) is a member of the Grb7 adaptor protein family that includes Grb10 and Grb14 proteins
GST-tagged Pin1 recombinant protein (GST-Pin1) purified from E. coli was capable of efficiently pulling down Grb7 (Fig 1D)
In addition to the pharmacological inhibition of JNK activity, we found that the interaction between Pin1 and Grb7 was significantly reduced in the MAPK8 knockdown cells compared to the mock control cells (Fig 3B)
Summary
Growth factor receptor bound protein 7 (Grb7) is a member of the Grb adaptor protein family that includes Grb and Grb proteins. The entire Grb family proteins are composed of five major protein-binding modules, including an N-terminal proline-rich region, a putative RA (Ras-associating) domain, a central PH (pleckstrin homology) domain, a BPS motif (between PH and SH2 domains), and a C-terminal SH2 domain [1,2,3]. Devoid of any enzymatic activity, these protein-binding modules enable Grb through simultaneous interactions with growth and/or adhesion receptors as well as intracellular proteins. Such interaction further facilitates the formation of signaling complexes involved in multiple signal transduction cascades that set forth to regulate diverse cellular functions [1, 2]. The physiological roles of these interactions are defined under certain pathological states, the detailed molecular mechanism of Grb regulation has not yet been elucidated.
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