Crosstalk between mTORC1 and cAMP Signaling
Abstract
Mutations in TSC1 and TSC2 genes are responsible for the majority of tuberous sclerosis complex (TSC). The major function of TSC1/2 is to inhibit mTORC1. Therefore, uncontrolled mTORC1 activation is a key molecular basis for TSC and TORC1 inhibitors is being used for TSC related complication. We discovered that mTORC1 can be inhibited by intracellular cAMP. We further found that the protein kinase A (PKA) mediates the effect of cAMP to inhibit mTORC1. Overexpression of the catalytic subunit of PKA leads to reduced mTORC1 activity while inhibition of PKA by pharmacological inhibitors blocks the inhibitory effect of cAMP on mTORC1. Furthermore, we found that cAMP and PKA function to prevent mTOR lysosomal localization, which is a process critical for mTORC1 activation. Our studies reveal a potential mechanism and future research direction how PKA inhibits mTORC1. This project also connects the two major intracellular signaling pathways, cAMP and mTOR, in the regulation of cell growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2014
- Accession Number
- ADA612068
Entities
People
- Kun-liang Guan
Organizations
- University of California, San Diego