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RhSTIP1 induced SAMD1/5 pathway

ABSTRACT: Stress-induced phosphoprotein 1 (STIP1), a co-chaperone that organizes other chaperones- heat shock proteins (HSP), was recently shown to be secreted by human ovarian cancer cells to induce cell proliferation. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular regulated MAP kinase) signaling pathways. However, in this study, we found that STIP1 stimulated cell proliferation of ovarian cancer via a bone morphogenetic protein (BMP) signaling pathway, not through the prion-ERK pathway. The STIP1 binding to a BMP receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate cancer cell proliferation. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3) that promotes cell proliferation. In conclusion, ovarian cancer tissues secrete STIP1 into the local environment and eventually into blood circulation of patients. In an autocrine and/or paracrine fashion, secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Elucidation of the mechanism by which STIP1 stimulates cancer cell proliferation may pave the way for developing novel therapeutic strategies for treatment of ovarian cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36383 | GEO | 2013/03/09

SECONDARY ACCESSION(S): PRJNA153269

REPOSITORIES: GEO

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rhSTIP1 induced SAMD1/5 pathway

Project description:Stress-induced phosphoprotein 1 (STIP1), a co-chaperone that organizes other chaperones- heat shock proteins (HSP), was recently shown to be secreted by human ovarian cancer cells to induce cell proliferation. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular regulated MAP kinase) signaling pathways. However, in this study, we found that STIP1 stimulated cell proliferation of ovarian cancer via a bone morphogenetic protein (BMP) signaling pathway, not through the prion-ERK pathway. The STIP1 binding to a BMP receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate cancer cell proliferation. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3) that promotes cell proliferation. In conclusion, ovarian cancer tissues secrete STIP1 into the local environment and eventually into blood circulation of patients. In an autocrine and/or paracrine fashion, secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Elucidation of the mechanism by which STIP1 stimulates cancer cell proliferation may pave the way for developing novel therapeutic strategies for treatment of ovarian cancer. SKOV3 cell,treated without rhSTIP1 SKOV3 cell,treated with rhSTIP1 SKOV3 cell,treated without rhSTIP1-2 SKOV3 cell,treated with rhSTIP1-2

2013-03-09 | E-GEOD-36383 | biostudies-arrayexpress

Secreted STIP1 stimulates cell proliferation of ovarian cancer through SMAD signaling pathways

Project description:Stress-induced phosphoprotein 1 (STIP1) is a co-chaperone that regulates other chaperone proteins that was recently shown to be secreted by ovarian cancer cells to induce cell proliferation. In this study, we found that STIP1 induced the phosphorylation of endogenous SMAD1/5, and knockdown of SMAD1/4/5 blocked STIP1-activated ID3 expression. Inhibition of ALK2, a serine/threonine kinase receptor, with siRNA or the specific inhibitor LDN193189, blocked STIP1-induced phosphorylation of SMAD1/5 and inhibited STIP1-related cell proliferation. The signaling pathway was found to involve binding of secreted STIP1 to ALK2, phosphorylation of SMAD, and activation of ID3 to induce cell proliferation was identified not only by in vitro immunofluorescent microscopy and biochemical identification of complex formation, but also by in vivo immunohistochemical analyses of ovarian cancer tissues. MDAH2774 cell treated with rhSTIP1 MDAH2774 cell treated without rhSTIP1 MDAH2774 cell treated with rhSTIP1-2 MDAH2774 cell treated without rhSTIP1-2

2012-03-03 | E-GEOD-27654 | biostudies-arrayexpress

Secreted STIP1 stimulates cell proliferation of ovarian cancer through SMAD signaling pathways

2012-03-03 | GSE27654 | GEO

Homo sapiens

Project description:Secreted STIP1 stimulates cell proliferation of ovarian cancer through SMAD signaling pathways

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Gene expression profiling of Activin-like kinase 2 knockout in mice

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Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

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Quantitative proteomics of the SMAD transcription factor family reveals IPO5 as a BMP Receptor-SMAD specific importin

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Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling

Project description:Loss of TGF-beta growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-beta resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich protein (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers, such as Hepatocellular carcinoma (HCC). In this study, we identified SFPQ as a potent suppressor of TGF-beta signaling. The ability of SFPQ to suppress TGF-beta responses depended on its prion-like domain (PrLD) that drives phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy, and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of LLPS rendered cells hypersensitive to TGF-beta responses. Together, our data reveal a unique function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-beta tumor-suppressive activity.

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