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Stk40 deletion enhances c-Jun protein stability and compromises mesoderm differentiation

ABSTRACT: Serine/threonine kinase 40 (Stk40) was previously identified as a direct target gene of pluripotency-associated transcription factor Oct4 and its overexpression could facilitate differentiation of mouse embryonic stem cells (mESCs) towards the extraembryonic endoderm. Stk40-/- mice are lethal at the perinatal stage, displaying multiple organ failures. However, the molecular mechanisms underlying the physiological functions of Stk40 remain elusive. Here, we report that Stk40 ablation compromises the mesoderm differentiation from mESCs in vitro and in embryos. Mechanistically, Stk40 interacts with both mammalian constitutive photomorphogenic protein 1 (Cop1) and c-Jun, promoting degradation of c-Jun. Consequently, Stk40 knockout leads to c-Jun protein accumulation, which, in turn, might suppress the Wnt signaling activity and impair the mesoderm differentiation process. Overall, this study reveals that Stk40, together with Cop1, represent a novel axis for modulating c-Jun protein levels within an appropriate range during mesoderm differentiation from mESCs. Our finding provides new insight into the molecular mechanism regulating c-Jun protein stability and may have potential for managing related cellular disorders.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Xiaofei Liu

LAB HEAD: Ying Jin

PROVIDER: PXD012579 | Pride | 2019-05-14

REPOSITORIES: Pride

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			Action	DRS
	mouse-stk40-shanghai-SCX2point1mm-TMT6-205min-1-5.raw	Raw
	mouse-stk40-shanghai-SCX2point1mm-TMT6-205min-10-5.raw	Raw
	mouse-stk40-shanghai-SCX2point1mm-TMT6-205min-12.raw	Raw
	mouse-stk40-shanghai-SCX2point1mm-TMT6-205min-13-5.raw	Raw
	mouse-stk40-shanghai-SCX2point1mm-TMT6-205min-15.raw	Raw

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Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation

Project description:Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) towards the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in the mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo. Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses the WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.

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