Katoh Masuko, Katoh Masaru
M and M Medical BioInformatics, Hongo, Japan.
Clin Cancer Res. 2007 Jul 15;13(14):4042-5. doi: 10.1158/1078-0432.CCR-06-2316.
WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the beta-catenin signaling cascade. Microtubule affinity-regulating kinase (PAR-1) family kinases, casein kinase I epsilon (CKI epsilon), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKI alpha, NKD1, NKD2, beta TRCP1, beta TRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator-activated receptor gamma (PPAR gamma) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, beta-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH(2)-terminal kinase) or the Ca(2+)-dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor beta/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPAR gamma agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT signaling pathway could be used in cancer medicine.
WNT信号被转导至经典途径以决定细胞命运，转导至非经典途径以控制细胞运动和组织极性。经典WNT信号通过卷曲蛋白家族受体和低密度脂蛋白受体相关蛋白5/6（LRP5/LRP6）共受体转导至β-连环蛋白信号级联反应。微管亲和力调节激酶（PAR-1）家族激酶、酪蛋白激酶Iε（CKIε）和FRAT是经典WNT途径的正调节因子，而腺瘤性息肉病蛋白（APC）、轴抑制蛋白1（AXIN1）、轴抑制蛋白2（AXIN2）、CKIα、NKD1、NKD2、β-转导素重复序列包含蛋白1（βTRCP1）、β-转导素重复序列包含蛋白2（βTRCP2）、锚蛋白重复结构域蛋白6（ANKRD6）、类Nemo样激酶（NLK）和过氧化物酶体增殖物激活受体γ（PPARγ）是负调节因子。由T细胞因子/淋巴细胞增强因子、β-连环蛋白、BCL9/BCL9L和PYGO组成的核复合物激活经典WNT靶基因如成纤维细胞生长因子20（FGF20）、 Dickkopf相关蛋白1（DKK1）、富含半胱氨酸的WNT诱导信号通路蛋白1（WISP1）、原癌基因c-Myc（MYC）、细胞周期蛋白D1（CCND1）和胰高血糖素（GCG）的转录。非经典WNT信号通过卷曲蛋白家族受体和受体酪氨酸激酶样孤儿受体2/受体酪氨酸激酶（ROR2/RYK）共受体转导至依赖于散乱蛋白的（Rho家族GTP酶和c-Jun氨基末端激酶）或依赖于钙离子的（NLK和活化T细胞核因子）信号级联反应。基于WNT、分泌型卷曲相关蛋白（SFRP）、WNT抑制因子（WIF）、DKK、卷曲蛋白受体、共受体的表达谱以及细胞内WNT信号调节因子的活性，WNT信号在不同情况下被转导至这两条途径。经典WNT途径负调节因子的表观遗传沉默和功能丧失突变发生在多种人类癌症中。WNT、成纤维细胞生长因子（FGF）、Notch、刺猬因子和转化生长因子β/骨形态发生蛋白信号网络通过调节正常干细胞的自我更新以及祖细胞（过渡放大细胞）的增殖或分化参与维持组织稳态。干细胞信号网络的破坏导致癌症发生。具有抑制经典WNT信号途径潜力的非甾体抗炎药和PPARγ激动剂是化学预防的候选药物。ZTM000990和PKF118-310是靶向经典WNT信号级联反应的先导化合物。抗WNT1和抗WNT2单克隆抗体在癌症治疗中显示出体外效应。经过优化后，靶向WNT信号途径的小分子化合物衍生物和人单克隆抗体可用于癌症医学。
