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SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis.

ABSTRACT: We previously reported that the protein-tyrosine phosphatase SHP-1 (PTPN6) negatively regulates insulin signaling, but its impact on hepatic glucose metabolism and systemic glucose control remains poorly understood. Here, we use co-immunoprecipitation assays, chromatin immunoprecipitation sequencing, in silico methods, and gluconeogenesis assay, and found a new mechanism whereby SHP-1 acts as a coactivator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene to increase liver gluconeogenesis. SHP-1 is recruited to the regulatory regions of the PCK1 gene and interacts with RNA polymerase II. The recruitment of SHP-1 to chromatin is dependent on its association with the transcription factor signal transducer and activator of transcription 5 (STAT5). Loss of SHP-1 as well as STAT5 decrease RNA polymerase II recruitment to the PCK1 promoter and consequently PCK1 mRNA levels leading to blunted gluconeogenesis. This work highlights a novel nuclear role of SHP-1 as a key transcriptional regulator of hepatic gluconeogenesis adding a new mechanism to the repertoire of SHP-1 functions in metabolic control.

SUBMITTER: Kumar A

PROVIDER: S-EPMC10504565 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis.

Kumar Amit A Schwab Michael M Laborit Labrada Beisy B Silveira Maruhen Amir Datsch MAD Goudreault Marilyn M Fournier Éric É Bellmann Kerstin K Beauchemin Nicole N Gingras Anne-Claude AC Bilodeau Steve S Laplante Mathieu M Marette André A

The Journal of biological chemistry 20230816 9

We previously reported that the protein-tyrosine phosphatase SHP-1 (PTPN6) negatively regulates insulin signaling, but its impact on hepatic glucose metabolism and systemic glucose control remains poorly understood. Here, we use co-immunoprecipitation assays, chromatin immunoprecipitation sequencing, in silico methods, and gluconeogenesis assay, and found a new mechanism whereby SHP-1 acts as a coactivator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene to increase liver ...[more]

PMID: 37595871

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Dataset Information

SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis.

Publications

SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis.

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