Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • GSK2801 Three main mechanisms have been proposed for the sec

    2022-05-04

    Three main mechanisms have been proposed for the secretion of active forms of hedgehog ligands: first, construction of a multimeric molecule with lipid moieties placed on the inside, making a soluble Hh protein which can diffuse from the membrane; second, function of dispatched proteins through packaging multimeric Hh or proton promoting transportation and third, movement of multimeric Hh by Tout-velo dependent mechanisms [40]. Subsequently, Hh ligands bind to their transmembrane receptors PTCH 1 and 2 or a G-protein-coupled-receptor resembling protein (GPCR GSK2801 class F) named Smo [41]. Specific co-receptors such as cell adhesion molecules may also be down-regulated by oncogenes such as (Cdo), brother of Cdo (Boc), and growth arrest–specific gene 1 (GAS-1), co-receptors which enhance the Hh ligand binding to PTCH. Contrarily, Hhip protein competes with Hh ligands for PTCH binding [34,42,43].
    Canonical hedgehog signaling pathway The canonical signaling pathway is mainly activated by binding modified Hh ligands to their PTCH receptor, hindering the inhibitory effect of PTCH on Smo, and allowing Smo to enter the primary cilium to regulate the downstream cascade. Smo generates intracellular signals which activate glioma-associated (Gli) transcription factors by modulating membrane associated protein complexes containing the protein kinase Fused (Fu), suppressor of Fused (SuFu) and the kinesin related protein costal 2 (Cos2). While the function of Fu in mammals is unclear, SuFu plays a significant role in regulating the stability of Gli factors in vertebrates, as a deficiency in these results in several development defects. SuFu forms complexes with Gli proteins which further accumulate in primary cilium following Hh stimulation, detaching after phosphorylation. These modified Gli proteins translocate from primary cilium to GSK2801 and from here to the nucleus, promoting expression of Hh target genes including Hh feedback pathway (e.g., GLI1, PTCH1), proliferation (e.g., MYC, Cyclin-D1), angiogenesis (e.g., ANG1/2), apoptosis (e.g., Bcl-2), epithelial-to-mesenchymal transition (EMT) (e.g., SNAIL), or stem cell self-renewal (e.g., NANOG, SOX2) [18,42,[44], [45], [46]]. The Gli family consists of three members: Gli 1, Gli 2, and Gli 3 through which the Hh target genes are regulated. A proteolytic process manipulates activity of Gli 3 and to some extent Gli 2 to display a dual function, both as repressors and activators of Hh target genes. When Hh stimulation is absent, proteolytic events remove the transactivation domain of Gli 3 in the primary cilium. The Gli 3 repressor protein then translocates to the nucleus, inhibiting the transcription of Hh target genes. Although the mechanism of Gli activator formation is yet to be entirely elucidated, some studies have proposed that this may occur through deactivation of G-protein-coupled receptor 161 (GPCR161) in the cilium, which further inhibits Hh signaling through PKA and Gli 3 repressor formation [47]. In contrast with Gli 2 and 3, Gli 1 is limited to activator functions.
    Non-canonical Hh signaling pathways
    Hedgehog signaling in cancer The activation of Hh signaling in a ligand independent manner, defined as Type I, is mainly determined by the acquisition of activator mutations within Smo, or inactivation mutations in the negative modulators - Sufu or Ptch1. These genomic modifications allow Hh cascade signaling without the presence of a specific ligand [59]. Patients with autosomal dominant disorders - BCNS (Gorlin syndrome) – frequently display a mutation of Ptch1; these patients are also associated with a high risk of acquiring sporadic basal cell carcinoma (BCC) and other malignancies such as medulloblastomas (MBs) and meningiomas [60]. Similarly, patients diagnosed with BCC or presence of MB had associated mutations in activators of inhibitors of Hh signaling [58]. Type II – the ligand dependent oncogenic Hh pathway (autocrine/juxtacrine mode)is, as the name suggests, activated upon ligand binding in a cell-autonomous manner, where production ligands can stimulate the activity of the cell of origin or of surrounding cells. Over-activation of such stimulation has been reported in numerous malignancies such as pancreatic, esophageal and stomach cancers [61], lung [62], prostate [63], breast [64] and colorectal cancers [65], melanoma [66] and glioma [67]. Colorectal cancer has been associated with contradictory results in terms of SHh expression; some studies report increased expression, suggesting that secretion of SHh is an essential feature of cancer development [68,69], while others concluded that the Hh pathway is inactive in this malignancy [61,70]. These contradictory data reports could highlight a tumor dependent context of Hh activation, where patient stratification could become an essential element in selection of potential experimental treatments.