Cancer cells feature increased de novo lipogenesis. Sterol regulatory 
element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), 
enhances lipogenesis by increasing transcription of several of its target genes. 
Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master 
regulators of cellular survival, growth and metabolism. A role for mTORC1 in the 
regulation of SREBP1 activity has been suggested; however, the connection 
between mTORC2 and SREBP1 has not been clearly established and hence is the 
focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit 
both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. 
Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, 
reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 
compared with parent or rictor-deficient cells with re-expression of ectopic 
rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a 
result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and 
fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells 
exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with 
INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin 
ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus 
mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 
degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 
positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a 
novel biological function of mTORC2 in the regulation of lipogenesis and warrant 
further study in this direction.