Katoh Yuriko, Katoh Masaru
M&M Medical Bioinformatics, Hongo 113-003, Japan.
Int J Mol Med. 2008 Sep;22(3):271-5.
SHH, IHH, and DHH are lipid-modified secreted proteins binding to Patched receptors, and CDON, BOC or GAS1 co-receptors. In the absence of Hedgehog signaling, GLI1 is transcriptionally repressed, GLI2 is phosphorylated by GSK3 and CK1 for the FBXW11 (betaTRCP2)-mediated degradation, and GLI3 is processed to a cleaved repressor. In the presence of Hedgehog signaling, Smoothened is relieved from Patched-mediated suppression due to the Hedgehog-dependent internalization of Patched, which leads to MAP3K10 (MST) activation and SUFU inactivation for the stabilization and nuclear accumulation of GLI family members. GLI activators then upregulate CCND1, CCND2 for cell cycle acceleration, FOXA2, FOXC2, FOXE1, FOXF1, FOXL1, FOXP3, POU3F1, RUNX2, SOX13, TBX2 for cell fate determination, JAG2, INHBC, and INHBE for stem cell signaling regulation. Hedgehog signals also upregulate SFRP1 in mesenchymal cells for WNT signaling regulation. Epithelial-to-mesenchymal transition (EMT) during embryogenesis, adult tissue homeostasis and carcinogenesis is characterized by class switch from E-cadherin to N-cadherin. SNAI1 (Snail), SNAI2 (Slug), SNAI3, ZEB1, ZEB2 (SIP1), KLF8, TWIST1, and TWIST2 are EMT regulators repressing CDH1 gene encoding E-cadherin. Hedgehog signals induce JAG2 upregulation for Notch-CSL-mediated SNAI1 upregulation, and also induce TGFbeta1 secretion for ZEB1 and ZEB2 upregulation via TGFbeta receptor and NF-kappaB. TGFbeta-mediated downregulation of miR-141, miR-200a, miR-200b, miR-200c, miR-205, and miR-429 results in upregulation of ZEB1 and ZEB2 proteins. Hedgehog signaling activation indirectly leads to EMT through FGF, Notch, TGFbeta signaling cascades, and miRNA regulatory networks. miRNAs targeted to stem cell signaling components or EMT regulators are potent drug targets; however, off-target effects should be strictly controlled before clinical application of synthetic miRNA. Peptide mimetic and RNA aptamer could also be utilized as Hedgehog signaling inhibitors or EMT suppressors.
音猬因子（SHH）、印度刺猬因子（IHH）和沙漠刺猬因子（DHH）是脂质修饰的分泌蛋白，可与patched受体以及CDON、BOC或GAS1共受体结合。在没有刺猬信号通路的情况下，GLI1受到转录抑制，GLI2被糖原合成酶激酶3（GSK3）和酪蛋白激酶1（CK1）磷酸化，进而通过FBXW11（β-转导素重复序列包含蛋白2，betaTRCP2）介导降解，而GLI3则被加工成一种裂解型阻遏物。在存在刺猬信号通路的情况下，由于patched依赖刺猬信号的内化作用，平滑受体（Smoothened）从patched介导的抑制中释放出来，这导致丝裂原活化蛋白激酶激酶激酶10（MAP3K10，MST）激活以及 Sufu 失活，从而使GLI家族成员得以稳定并在细胞核中积累。然后，GLI激活剂上调细胞周期蛋白D1（CCND1）、细胞周期蛋白D2（CCND2）以加速细胞周期，上调叉头框A2（FOXA2）、叉头框C2（FOXC2）、叉头框E1（FOXE1）、叉头框F1（FOXF1）、叉头框L1（FOXL1）、叉头框P3（FOXP3）、POU结构域3转录因子1（POU3F1）、 runt相关转录因子2（RUNX2）、SRY（Y染色体性别决定区）-盒13（SOX13）、T-box转录因子2（TBX2）以决定细胞命运，上调锯齿蛋白2（JAG2）、抑制素βC（INHBC）和抑制素βE（INHBE）以调节干细胞信号通路。刺猬信号还上调间充质细胞中的分泌型卷曲相关蛋白1（SFRP1）以调节WNT信号通路。胚胎发育、成体组织稳态和肿瘤发生过程中的上皮-间质转化（EMT）的特征是从E-钙黏蛋白向N-钙黏蛋白的类别转换。Snail家族转录抑制因子1（SNAI1，Snail）、Snail家族转录抑制因子2（SNAI2，Slug）、SNAI3、锌指E盒结合蛋白1（ZEB1）、锌指E盒结合蛋白2（ZEB2，SIP1）、 kruppel样因子8（KLF8）、TWIST家族bHLH转录因子1（TWIST1）和TWIST家族bHLH转录因子2（TWIST2）是EMT调节因子，可抑制编码E-钙黏蛋白的CDH1基因。刺猬信号诱导JAG2上调，从而通过Notch-CSL介导使SNAI1上调，还诱导转化生长因子β1（TGFbeta1）分泌，通过TGFbeta受体和核因子κB（NF-kappaB）使ZEB1和ZEB2上调。TGFbeta介导的微小RNA-141（miR-141）、微小RNA-200a（miR-200a）、微小RNA-200b（miR-200b）、微小RNA-200c（miR-200c）、微小RNA-205（miR-205）和微小RNA-429（miR-
