Dataset Information

Regulation of cytokine-inducible SH2-containing protein (CIS) by ubiquitination and Elongin B/C interaction.

ABSTRACT: Cytokine-inducible SH2-containing protein (CIS) inhibits prolactin receptor (PRLR) signaling and acts as part of an E3 ubiquitin ligase complex through interactions with Elongin B/C proteins. This study aimed to identify CIS lysine ubiquitination sites and determine roles of ubiquitination and Elongin B/C interactions on CIS protein stability and PRLR signaling inhibition. Site-directed mutations revealed that CIS can be ubiquitinated on all six lysine residues. Elongin B/C interaction box mutation had no influence on CIS ubiquitination. CIS stability was increased by mutation of lysine residues and further enhanced by co-mutation of Elongin B/C interaction domain. CIS inhibition of STAT5B phosphorylation and casein promoter activation was dependent on CIS interactions with Elongin B/C, but not on CIS ubiquitination. These data indicate CIS protein stability is regulated through multiple mechanisms, including ubiquitination and interaction with Elongin B/C proteins, whereas CIS functional inhibition of PRLR signaling is dependent on the Elongin B/C interaction.

SUBMITTER: Jensik PJ

PROVIDER: S-EPMC4373541 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Regulation of cytokine-inducible SH2-containing protein (CIS) by ubiquitination and Elongin B/C interaction.

Jensik Philip J PJ Arbogast Lydia A LA

Molecular and cellular endocrinology 20141104

Cytokine-inducible SH2-containing protein (CIS) inhibits prolactin receptor (PRLR) signaling and acts as part of an E3 ubiquitin ligase complex through interactions with Elongin B/C proteins. This study aimed to identify CIS lysine ubiquitination sites and determine roles of ubiquitination and Elongin B/C interactions on CIS protein stability and PRLR signaling inhibition. Site-directed mutations revealed that CIS can be ubiquitinated on all six lysine residues. Elongin B/C interaction box mutat ...[more]

PMID: 25448846

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Project description:BackgroundWe have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence.ObjectiveTo determine the effect of SHP2 on fibrotic responses.Methods and resultsPrimary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H2O2 stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2+/+). SHP2 D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy.ConclusionsSHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

Dataset Information

Regulation of cytokine-inducible SH2-containing protein (CIS) by ubiquitination and Elongin B/C interaction.

Publications

Regulation of cytokine-inducible SH2-containing protein (CIS) by ubiquitination and Elongin B/C interaction.

Similar Datasets

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