AKAP13 couples GPCR signaling to mTORC1 inhibition

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. mTORC1 is typically hyperactivated in multiple human diseases such as cancer and type 2 diabetes. Extensive research has focused on signaling pathways that can activate mTORC1 such as growth factors and amino acids. However, less is known about signaling cues that can directly inhibit mTORC1 activity. Here, we identify A-kinase anchoring protein 13 (AKAP13) as an mTORC1 binding protein, and a crucial regulator of mTORC1 inhibition by G-protein coupled receptor (GPCR) signaling. GPCRs paired to Gαs proteins increase cyclic adenosine 3’5’ monophosphate (cAMP) to activate protein kinase A (PKA). Mechanistically, AKAP13 acts as a scaffold for PKA and mTORC1, where PKA inhibits mTORC1 through the phosphorylation of Raptor on Ser 791. Importantly, AKAP13 mediates mTORC1-induced cell proliferation, cell size, and colony formation. AKAP13 expression correlates with mTORC1 activation and overall lung adenocarcinoma patient survival, as well as lung cancer tumor growth in vivo. Our study identifies AKAP13 as an important player in mTORC1 inhibition by GPCRs, and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1.

Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity

“…A recent study showed that AKAP13 inhibits mammalian target of rapamycin complex 1 (mTORC1), which was present in our enrichment analysis as “mTOR signaling pathway” ( Table 3 ). Furthermore, the degree of AKAP13 expression in lung adenocarcinoma cell lines correlates with mTORC1 activity [ 35 ]. Metformin’s anti-inflammatory effect has been shown to occur through eventual AMPK activation, which also inhibits the mTOR signaling pathway [ 18 ].…”

Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity

“…A recent study showed that AKAP13 inhibits mammalian target of rapamycin complex 1 (mTORC1), which was present in our enrichment analysis as "mTOR signaling pathway" (Table 3). Furthermore, the degree of AKAP13 expression in lung adenocarcinoma cell lines correlates with mTORC1 activity 36 . Metformin's anti-inflammatory effect has been shown to occur though eventual AMPK activation, which also inhibits the mTOR signaling pathway (34).…”

G-Protein Coupled Receptor Signaling and Mammalian Target of Rapamycin Complex 1 Regulation

“…AKAP13 scaffolds PKA next to mTORC1, leading to Raptor Ser791 phosphorylation and mTORC1 inhibition. Additionally, AKAP13 plays a role in the mTORC1-mediated processes of cell proliferation, cell size, and lung tumorigenesis ( Zhang et al, 2021 ). Previous studies found that AKAP13 promotes ERK signaling ( Smith et al, 2010 ) and displays GEF activity for RhoA, promoting activation of p38 α ( Pérez López et al, 2013 ).…”

“…ERK signaling is known to activate mTORC1 by inhibiting TSC ( Ma et al, 2005 ), and p38 α has been previously reported to negatively alter TSC function by promoting TSC and 14-3-3 binding ( Li et al, 2003 ; Shumway et al, 2003 ). However, the pharmacological inhibition of ERK signaling did not change Raptor Ser 791 phosphorylation, and p38 α depletion did not alter mTORC1 activity ( Zhang et al, 2021 ). Similarly, it was found that TSC knockout cells also did not affect Raptor Ser791 phosphorylation ( Jewell et al, 2019 ), indicating that AKAP13-mediated regulation of mTORC1 may be independent of ERK and p38 α signaling.…”