Background: Dual specificity protein phosphatases (DSPs) bind MAPKs through specific interaction motifs

Dickinson, Robin J.

Didmon, Mark P.

Jose Marin, Maria

Keyse, Stephen M.

Martin, Humberto

Molina, Maria

Palacios, Lorena

Sacristan-Reviriego, Almudena

PubMed

Lorena Palacios

Robin J. Dickinson

Almudena Sacristán-Reviriego

Mark P. Didmon

María José Marín

Humberto Martín

Stephen M. Keyse

María Molina

Crossref

Journal of Biological Chemistry

Distinct Docking Mechanisms Mediate Interactions between the Msg5 Phosphatase and Mating or Cell Integrity Mitogen-activated Protein Kinases (MAPKs) in Saccharomyces cerevisiae

MAPK phosphatases (MKPs) are negative regulators of signaling pathways with distinct MAPK substrate specificities. For example, the yeast dual specificity phosphatase Msg5 dephosphorylates the Fus3 and Slt2 MAPKs operating in the mating and cell wall integrity pathways, respectively. Like other MAPKinteracting proteins, most MKPs bind MAPKs through specific docking domains. These include D-motifs, which contain basic
residues that interact with acidic residues in the common docking (CD) domain of MAPKs. Here we show that Msg5 interacts not only with Fus3, Kss1, and Slt2 but also with the pseudokinase Slt2 paralog Mlp1. Using yeast two-hybrid and in vitro interaction assays, we have identified distinct regions within the N-terminal domain of Msg5 that differentially bind either the MAPKs Fus3 and Kss1 or Slt2 and Mlp1. Whereas a canonical D-site within Msg5 mediates interaction with the CD domains of Fus3 and Kss1, a novel motif (102IYT104) within Msg5 is
involved in binding to Slt2 and Mlp1. Furthermore, mutation of this site prevents the phosphorylation of Msg5 by Slt2. This motif is conserved in Sdp1, another MKP that dephosphorylates Slt2, as well as in Msg5 orthologs from other yeast species. A region spanning amino acids 274–373 within Slt2 and Mlp1 mediates binding to this Msg5 motif in a CD domain-independent manner. In contrast, Slt2 uses its CD domain to bind to its
upstream activator Mkk1. This binding flexibility may allow MAPK pathways to exploit additional regulatory controls in order to provide fine modulation of both pathway activity and specificity.Ministerio de Ciencia e Innovación (España)Cancer Research UK ProgramDepto. de Microbiología y ParasitologíaFac. de FarmaciaTRUEpu

Sacristán Reviriego, Almudena

Marín Cuenda, María José

Martín Brieva, Humberto

Molina Martín, María

Docta Complutense

MAPK phosphatases (MKPs) are negative regulators of signaling pathways with distinct MAPK substrate specificities. For example, the yeast dual specificity phosphatase Msg5 dephosphorylates the Fus3 and Slt2 MAPKs operating in the mating and cell wall integrity pathways, respectively. Like other MAPK-interacting proteins, most MKPs bind MAPKs through specific docking domains. These include D-motifs, which contain basic residues that interact with acidic residues in the common docking (CD) domain of MAPKs. Here we show that Msg5 interacts not only with Fus3, Kss1, and Slt2 but also with the pseudokinase Slt2 paralog Mlp1. Using yeast two-hybrid and in vitro interaction assays, we have identified distinct regions within the N-terminal domain of Msg5 that differentially bind either the MAPKs Fus3 and Kss1 or Slt2 and Mlp1. Whereas a canonical D-site within Msg5 mediates interaction with the CD domains of Fus3 and Kss1, a novel motif ((IYT104)-I-102) within Msg5 is involved in binding to Slt2 and Mlp1. Furthermore, mutation of this site prevents the phosphorylation of Msg5 by Slt2. This motif is conserved in Sdp1, another MKP that dephosphorylates Slt2, as well as in Msg5 orthologs from other yeast species. A region spanning amino acids 274-373 within Slt2 and Mlp1 mediates binding to this Msg5 motif in a CD domain-independent manner. In contrast, Slt2 uses its CD domain to bind to its upstream activator Mkk1. This binding flexibility may allow MAPK pathways to exploit additional regulatory controls in order to provide fine modulation of both pathway activity and specificity.</p

Discovery Research Portal

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3234975

Distinct Docking Mechanisms Mediate Interactions between the Msg5 Phosphatase and Mating or Cell Integrity Mitogen-activated Protein Kinases (MAPKs) in Saccharomyces cerevisiae

Abstract

Similar works

Full text

Available Versions

Crossref

Docta Complutense

Discovery Research Portal

Discovery Research Portal