Dataset Information

Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38? by the dual specificity phosphatase 16 MAP kinase binding domain in solution.

ABSTRACT: Mitogen-activated protein kinases (MAPKs) fulfill essential biological functions and are key pharmaceutical targets. Regulation of MAPKs is achieved via a plethora of regulatory proteins including activating MAPKKs and an abundance of deactivating phosphatases. Although all regulatory proteins use an identical interaction site on MAPKs, the common docking and hydrophobic pocket, they use distinct kinase interaction motif (KIM or D-motif) sequences that are present in linear, peptide-like, or well folded protein domains. It has been recently shown that a KIM-containing MAPK-specific dual specificity phosphatase DUSP10 uses a unique binding mode to interact with p38?. Here we describe the interaction of the MAPK binding domain of DUSP16 with p38? and show that despite belonging to the same dual specificity phosphatase (DUSP) family, its interaction mode differs from that of DUSP10. Indeed, the DUSP16 MAPK binding domain uses an additional helix, ?-helix 4, to further engage p38?. This leads to an additional interaction surface on p38?. Together, these structural and energetic differences in p38? engagement highlight the fine-tuning necessary to achieve MAPK specificity and regulation among multiple regulatory proteins.

SUBMITTER: Kumar GS

PROVIDER: S-EPMC3784751 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38α by the dual specificity phosphatase 16 MAP kinase binding domain in solution.

Kumar Ganesan Senthil GS Zettl Heiko H Page Rebecca R Peti Wolfgang W

The Journal of biological chemistry 20130807 39

Mitogen-activated protein kinases (MAPKs) fulfill essential biological functions and are key pharmaceutical targets. Regulation of MAPKs is achieved via a plethora of regulatory proteins including activating MAPKKs and an abundance of deactivating phosphatases. Although all regulatory proteins use an identical interaction site on MAPKs, the common docking and hydrophobic pocket, they use distinct kinase interaction motif (KIM or D-motif) sequences that are present in linear, peptide-like, or wel ...[more]

PMID: 23926106

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Project description:The BRAF-MKK1/2-ERK1/2 pathway is constitutively activated in response to oncogenic mutations of BRAF in many cancer types, including melanoma. Although small molecules that inhibit oncogenic BRAF and MAP kinase kinase (MKK)1/2 have been successful in clinical settings, resistance invariably develops. High affinity inhibitors of ERK1/2 have been shown in preclinical studies to bypass the resistance of melanoma and colon cancer cells to BRAF and MKK1/2 inhibitors, and are thus promising additions to current treatment protocols. But still unknown is how molecular responses to ERK1/2 inhibitors compare with inhibitors currently in clinical use. Here, we employ quantitative phosphoproteomics to evaluate changes in phosphorylation in response to the ERK inhibitors, SCH772984 and GDC0994, and compare these to the clinically used MKK1/2 inhibitor, trametinib. Combined with previous studies measuring phosphoproteomic responses to the MKK1/2 inhibitor, selumetinib, and the BRAF inhibitor, vemurafenib, the outcomes reveal key insights into pathway organization, phosphorylation specificity and off-target effects of these inhibitors. The results demonstrate linearity in signaling from BRAF to MKK1/2 and from MKK1/2 to ERK1/2. They identify likely targets of direct phosphorylation by ERK1/2, as well as inhibitor off-targets, including an off-target regulation of the p38α mitogen activated protein kinase (MAPK) pathway by the MKK1/2 inhibitor, trametinib, at concentrations used in the literature but higher than in vivo drug concentrations. In addition, several known phosphorylation targets of ERK1/2 are insensitive to MKK or ERK inhibitors, revealing variability in canonical pathway responses between different cell systems. By comparing multiple inhibitors targeted to multiple tiers of protein kinases in the MAPK pathway, we gain insight into regulation and new targets of the oncogenic BRAF driver pathway in cancer cells, and a useful approach for evaluating the specificity of drugs and drug candidates.

Dataset Information

Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38? by the dual specificity phosphatase 16 MAP kinase binding domain in solution.

Publications

Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38α by the dual specificity phosphatase 16 MAP kinase binding domain in solution.

Similar Datasets

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