Inhibition of Ras, Hippo, and NF-κB signaling by Merlin. (A) Merlin’s role in inhibiting Ras signaling: Ras, a G-protein, shifts between inactive GDP-bound and active GTP-bound states, impacting cell proliferation and division. Active Ras connects with multiple effectors, initiating downstream signaling like Ras/Raf/MAPK and Ras/PI3K/Akt pathways, driving cellular transformation and tumorigenesis. Ras activation also triggers Rac/Cdc42 and their downstream PAK1, which phosphorylates Merlin and inactivates it. MYPT1 protects Merlin by keeping it in a dephosphorylated state, while CPI-17 inhibits MYPT1, leading to Merlin phosphorylation. Merlin counteracts Ras-induced transformation through various mechanisms. (B) Merlin’s role in inhibiting Hippo signaling: Merlin directly activates STE20-like protein (MST1/2), which, in turn, phosphorylates large tumor suppressor homolog 1/2 (LATS1/2). Merlin also inhibits the CRL4/DCAF1 complex-mediated degradation of LATS1/2. Activated LATS1/2 directly phosphorylates YAP and its transcriptional co-activator TAZ, leading to ubiquitination-mediated degradation and resulting in the inhibition of Hippo signaling. (C) Merlin’s role in inhibiting NF-κB signaling: NF-κB comprises homo- and heterodimeric proteins (p65/RelA, c-Rel, p50/p105 [NF-κB1], and RelB and p52/p100 [NF-κB2]) within cells, residing in nonstimulated cell cytoplasm bound to IκB. Inflammatory cytokines or growth factors activate NF-κB signaling, inducing the transcription of genes involved in numerous cellular processes. Merlin inhibits NF-κB signaling by blocking p65, NIK, IKKα, TNF-α-induced IκB degradation, and NF-κB–DNA binding, subsequently inhibiting transcription.