Abstract
We have previously demonstrated that the Src family kinase Yes, the Yes-associated protein (YAP) and TEA domain TEAD2 transcription factor pathway are activated by leukemia inhibitory factor (LIF) and contribute to mouse embryonic stem (mES) cell maintenance of pluripotency and self-renewal. In addition, we have shown that fetal bovine serum (FBS) induces Yes auto-phosphorylation and activation. In the present study we confirm that serum also activates TEAD-dependent transcription in a time- and dose-dependent manner and we identify Inter-α-inhibitor (IαI) as a component in serum capable of activating the Yes/YAP/TEAD pathway by inducing Yes auto-phosphorylation, YAP nuclear localization and TEAD-dependent transcription. The cleaved heavy chain 2 (HC2) sub-component of IαI, is demonstrated to be responsible for this effect. Moreover, IαI is also shown to efficiently increase expression of TEAD-downstream target genes including well-known stem cell factors Nanog and Oct 3/4. IαI is not produced by the ES cells per se but is added to the cells via the cell culture medium containing serum or serum-derived components such as bovine serum albumin (BSA). In conclusion, we describe a novel function of IαI in activating key pluripotency pathways associated with ES cell maintenance and self-renewal.
Highlights
Serum contributes to embryonic stem (ES) cell maintenance of pluripotency and activates Yes
We have previously demonstrated that the Src family kinase Yes, the Yes-associated protein (YAP) and TEA domain TEAD2 transcription factor pathway are activated by leukemia inhibitory factor (LIF) and contribute to mouse embryonic stem cell maintenance of pluripotency and self-renewal
Many cytokines and extracellular matrix proteins have been identified in serum as key factors for the induction of proliferation and attachment, but many others remain to be studied for their effect on cell culture
Summary
Serum contributes to embryonic stem (ES) cell maintenance of pluripotency and activates Yes. Results: The serum protein Inter-␣-inhibitor (I␣I) was found to activate the Yes/YAP/TEAD transcription factor pathway and induce expression of Oct3/4 and Nanog in ES cells. We have previously demonstrated that the Src family kinase Yes, the Yes-associated protein (YAP) and TEA domain TEAD2 transcription factor pathway are activated by leukemia inhibitory factor (LIF) and contribute to mouse embryonic stem (mES) cell maintenance of pluripotency and self-renewal. We here show that I␣I purified from human plasma, as well as cleaved HC2, but not HC1, activate the Yes/YAP/TEAD2 pathway and induce expression of the pluripotent stem cell transcription factors Nanog and TEAD target genes Oct3/4, Cyr, and CTGF
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