SGK196 controls stem cell fates by promoting the degradation of TGFβ family receptors

SGK196;cell signaling;TGFβ family signaling pathway;transmembrane domain;human embryonic stem cells;cell fate

Tsang Mui Chung, Stephanie

关键词: SGK196;    cell signaling;    TGFβ family signaling pathway;    transmembrane domain;    human embryonic stem cells;    cell fate;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/72931/Stephanie_Tsang%20Mui%20Chung.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Much remains to be understood regarding the molecular mechanisms controlling stem cell fate.Through studies in human pluripotent stem cells (hPSCs), I have identified SGK196, an atypical kinase of relatively unknown function, as a novel regulator of cell fate and the TGFβ family signaling pathway.SGK196 depletion in human embryonic stem cells (hESCs) inhibits neural induction and enhances mesoderm induction, while SGK196 overexpression represses mesoderm and endoderm induction.SGK196 negatively regulates TGFβ family signaling by interacting with and promoting the degradation of TGFβ family receptors.Interactions were observed to occur within the SGK196 transmembrane (TM) domain.Mutation of specific Asn, Asp, and His residues in the SGK196 TM domain resulted in the diminished degradation of TGFβ family receptors and reduced interactions with the type I BMP receptor (BMPR1B), suggesting that these polar residues may play a key role in arbitrating SGK196 activity.The functional effects of Sgk196 in Xenopus laevis animal caps and embryos are in agreement with the results in hESCs.Defects in Sgk196 depleted Xenopus embryos include impaired development of neural tissues and increased development of mesodermal tissues.Overall, I demonstrate that SGK196 is an essential regulator of stem cell fate determination and early development. Through uncovering the regulatory mechanism of SGK196 I unveil valuable insight into receptor-level regulation of the TGFβ family pathway.