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. 2023 Feb 16;14:1109491. doi: 10.3389/fgene.2023.1109491

FIGURE 2.

FIGURE 2

Working model of confluent network summarizing GPCR/Rho/ROCK, RTK/Ras/MAPK, TGFβ/YAP/NF-κB/mTOR, IGFR/PI3K/mTOR, and HGF/MET pathways in UPS/MFS. (A). The decoupling of miR-138 from RHO-ROCK adhesion pathway promotes UPS cell migration; (B). miR-152 downexpression disinhibits target genes production with receptor tyrosine kinase activity, and thus upregulates the downstream MAPK signaling; (C). Hepatocyte growth factor/MET (HGF/MET) pathway was aberrantly activated due to its receptor overexpression. (D). The significant secretion of TGFβ cytokine by tumor-infiltrating macrophages (TAMs) in the sarcoma microenvironment activates downstream signaling; (E). Yes-associated protein (YAP) is constitutively activated by upstream pathways including TGFβ pathway; (F). TAZ and YAP are normally inhibited by Hippo pathway or Angiomotin (AMOT), but unusually stable in UPS/MFS; (G). YAP activates mTOR signaling, exhibiting NF-κB independent effect of on autophagy; (H). YAP controls the expression of ubiquitin specific protein 31 (USP31), and thus phosphorylated NF-κB persistently suppresses the circadian clock activity, leading to cellular metabolism shift and unfold protein response (UPR) dysfunction; (I). Stabilized YAP and TGFβ signaling cooperatively regulate hyaluronan-mediated motility receptor (RHAMM/HMMR) expression, enhancing sarcomagenesis and distant metastasis; (J). The complex between transcriptional co-activator with PDZ-binding motif (TAZ) and YAP translocate into the nucleus and upregulate FOXM1 expression, which is pro-growth factor in UPS/MFS; (K). The transcriptional product of ITAG10 is associated with RICTOR which is subunit of rapamycin complex 2 (mTORC2); (L). ITAG10 encodes TRIO, and promote cell survival via RAC/PAK signaling; (M). PPP2R2B encoding product directly interacts with PDK1 and suppresses AKT/mTOR signaling in UPS/MFS.