PRL-1 protein promotes ERK1/2 and RhoA protein activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTpase-activating protein

Yunpeng Bai, Yong Luo, Sijiu Liu, Lujuan Zhang, Kui Shen, Yuanshu Dong, Chad D. Walls, Lawrence A. Quilliam, Clark D. Wells, Youjia Cao, Zhong Yin Zhang

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27 Scopus citations


Phosphatases of the regenerating liver (PRL) play oncogenic roles in cancer development and metastasis. Although previous studies indicate that PRL-1 promotes cell growth and migration by activating both the ERK1/2 and RhoA pathways, the mechanism by which it activates these signaling events remains unclear.Wehave identified a PRL-1-binding peptide (Peptide 1) that shares high sequence identity with a conserved motif in the Src homology 3 (SH3) domain of p115 Rho GTPase-activating protein (GAP). p115 RhoGAP directly binds PRL-1 in vitro and in cells via its SH3 domain. Structural analyses of the PRL- 1Peptide 1 complex revealed a novel protein-protein interaction whereby a sequence motif within the PxxP ligand-binding site of the p115 RhoGAP SH3 domain occupies a folded groove within PRL-1. This prevents the canonical interaction between the SH3 domain of p115 RhoGAP and MEKK1 and results in activation of ERK1/2. Furthermore, PRL-1 binding activates RhoA signaling by inhibiting the catalytic activity of p115 RhoGAP. The results demonstrate that PRL-1 binding to p115 RhoGAP provides a coordinated mechanism underlying ERK1/2 and RhoA activation.

Original languageEnglish (US)
Pages (from-to)42316-42324
Number of pages9
JournalJournal of Biological Chemistry
Issue number49
StatePublished - Dec 9 2011


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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