Figure 6. Downstream Signaling of BVL and RL PTCs.
(A) MAPK and PI3K pathways are differentially activated in the BVL and RL PTCs.
(B) BRAFV600E-mutated cases show robust activation of MAPK signaling resulting in higher output of the ERK transcriptional program, represented in particular by DUSP (DUSP4, 5 and 6) mRNAs. This may be due to insensitivity of BRAFV600E to ERK inhibitory feedback. By contrast, RAS-like tumors activated both MAPK and PI3K/AKT signaling, as shown by higher pAKT levels in these tumors. The mechanism by which RAS-like tumors activated MAPK signaling was distinct from that of BRAFV600E tumors, as they had higher CRAF phosphorylation, consistent with engagement of RAF dimers. Paradoxically, RL-PTCs had higher phosphorylation of the ERK substrate p90RSK, which was associated with mTOR activation, likely through phosphorylation and consequent inhibition of TSC2. RL-PTCs also showed activation of an anti-apoptotic program, characterized by S112-BAD phosphorylation (a target of P90RSK) and BCL2 over-expression. See also Figures S8 and Tables S4B,F.