Potential Therapeutic Targets in Uterine Sarcomas

Figure 1

Left: the PI3K/AKT/mTOR pathway is mainly activated by nutrients (not shown) and growth factors, binding to receptor tyrosine kinases and activating PI3K. As PIP2 (phosphatidylinositol 4,5-bisphosphate) is converted to PIP3 (phosphatidylinositol 3,4,5-trisphosphate), PDK1 (pyruvate dehydrogenase kinase, isozyme 1) phosphorylates AKT1 (v-akt murine thymoma viral oncogene homolog 1) upon PIP3-mediated recruitment to the plasma membrane. AKT1 inhibits TSC1/2 (tuberous sclerosis 1/2), relieving the inhibition of Rheb (Ras homolog enriched in brain), which activates mTOR. The recruitment of Raptor (regulatory associated protein of MTOR, complex 1), Deptor (DEP domain containing MTOR-interacting protein), and GβL (mLST8; G protein beta subunit-like MTOR associated protein, LST8 homolog) gives rise to the mTOR complex 1 (mTORC1). Upon activation of S6K1 (ribosomal protein S6 kinase 1) and inhibition of 4EBP-1 (EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1), protein translation is stimulated by activation of ribosomal protein S6 and eIF4B and E (eukaryotic translation initiation factor 4B and E). Additionally, AKT1 activates β-catenin signaling. Middle: BMP (bone morphogenetic protein) signaling is modulated through binding of BMPs to BMPR1 and BMPR2 (bone morphogenetic protein receptor type I/II) and the coreceptor endoglin, activating Smad1/5/8 and leading to transcription of target genes involved in angiogenesis and proliferation. Endoglin may also activate PI3K/AKT signaling. Right: canonical Wnt signaling is activated by binding of Wnt to the Frizzled receptor and the LRP (low-density lipoprotein receptor-related protein) coreceptor. Upon recruitment of Dsh (dishevelled) and Axin to the plasma membrane, the β-catenin destruction complex, which contains Axin, APC (adenomatosis polyposis coli), GSK3 (glycogen synthase kinase 3), and CKI (casein kinase 1), is inactivated, leading to β-catenin accumulation and transcription of target genes after association with TCF/LEF (transcription factor/lymphoid enhancer-binding factor). Noncanonical signaling plays a role in cell migration, invasion, and cytoskeleton arrangement and is mediated through binding of Wnt to Frizzled and other coreceptors such as ROR2 (receptor tyrosine kinase-like orphan receptor 2) or without coreceptors.