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 Quilliam, Clark Wells, Youjia Cao, Zhong-Yin Zhang

Research output: Contribution to journalArticle

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Abstract

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
Pages (from-to)42316-42324
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number49
DOIs
StatePublished - Dec 9 2011

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rhoA GTP-Binding Protein
src Homology Domains
Phosphoric Monoester Hydrolases
Liver
Chemical activation
Proteins
Peptides
rho GTPase-activating protein
MAP Kinase Signaling System
Cell growth
Cell Movement
Catalyst activity
Binding Sites
Neoplasm Metastasis
Ligands

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 286, No. 49, 09.12.2011, p. 42316-42324.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - 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

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AU - Luo, Yong

AU - Liu, Sijiu

AU - Zhang, Lujuan

AU - Shen, Kui

AU - Dong, Yuanshu

AU - Walls, Chad D.

AU - Quilliam, Lawrence

AU - Wells, Clark

AU - Cao, Youjia

AU - Zhang, Zhong-Yin

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AB - 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.

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