Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dos Sarbassov

Committee Member

Xin Lin

Committee Member

Mong-Hong Lee

Committee Member

Georg Halder

Committee Member

Hui-Kuan Lin


Growth factor signaling promotes anabolic processes via activation of the

PI3K-Akt kinase cascade. Deregulation of the growth factor-dependent PI3K-Akt

pathway was implicated in tumorigenesis. Akt is an essential serine/threonine

protein kinase that controls multiple physiological functions such as cell growth,

proliferation, and survival to maintain cellular homeostasis. Recently, the

mammalian Target of Rapamycin Complex 2 (mTORC2) was identified as the

main Akt Ser-473 kinase, and Ser-473 phosphorylation is required for Akt

hyperactivation. However, the detailed mechanism of mTORC2 regulation in

response to growth factor stimulation or cellular stresses is not well understood.

In the first project, we studied the regulation of the mTORC2-Akt signaling

under ER stress. We identified the inactivation of mTORC2 by glycogen synthase

kinase-3β (GSK-3β). Under ER stress, the essential mTORC2 component, rictor,

is phosphorylated by GSK-3β at Ser-1235. This phosphorylation event results in

the inhibition of mTORC2 kinase activity by interrupting Akt binding to mTORC2.

Blocking rictor Ser-1235 phosphorylation can attenuate the negative impacts of

GSK-3β on mTORC2/Akt signaling and tumor growth. Thus, our work

demonstrated that GSK-3β-mediated rictor Ser-1235 phosphorylation in response

to ER stress interferes with Akt signaling by inhibiting mTORC2 kinase activity.

In the second project, I investigated the regulation of the mTORC2 integrity.

We found that basal mTOR kinase activity depends on ATP level, which is tightly

regulated by cell metabolism. The ATP-sensitive mTOR kinase is required for

SIN1 protein phosphorylation and stabilization. SIN1 is an indispensable subunit of

mTORC2 and is required for the complex assembly and mTORC2 kinase activity.

Our findings reveal that mTOR-mediated phosphorylation of SIN1 is critical for

maintaining complex integrity by preventing SIN1 from lysosomal degradation.

In sum, our findings verify two distinct mTORC2 regulatory mechanisms via

its components rictor and SIN1. First, GSK-3β-mediated rictor Ser-1235

phosphorylation results in mTORC2 inactivation by interfering its substrate binding

ability. Second, mTOR-mediated Ser-260 phosphorylation of SIN1 preserves its

complex integrity. Thus, these two projects provide novel insights into the

regulation of mTORC2.


cell signaling, mTORC2, Akt, GSK-3 beta, ER stress, complex integrity



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