CSF1（巨噬细胞集落刺激因子）介导的髓系细胞信号传导
中文名称
通路描述
CSF1（也称为巨噬细胞集落刺激因子，M-CSF）是一种二硫键连接的二聚体，刺激单核吞噬细胞系的增殖和分化，并促进巨噬细胞的生存、增殖、运动及抗炎活性。未配位的 CSF1 受体 CSF1R（CSF-1R）在细胞表面呈簇状分布或经历快速的二聚体 - 单体转换。CSF1 二聚体首先结合 CSF1R 单体 D2 和 D3 胞外结构域，随后第二个 CSF1R 单体结合 CSF1:CSF1R 复合物，导致 CSF1R 二聚化并激活其激酶活性。CSF1R 初始在胞内区酪氨酸 561 位发生自磷酸化，解除激酶活性的负自抑制，并在其胞内区进一步发生 7 次酪氨酸残基的自磷酸化。PI3K 的调节亚基 PIK3R1（p85alpha）结合 CSF1R 酪氨酸 723 位磷酸化残基，SRC 蛋白结合磷酸化酪氨酸 561 位，CBL 蛋白结合 CSF1R 并招募 SHC，GRB2:SOS 结合 CSF1R。PI3K 催化亚基的激活产生磷脂酰肌醇 3,4,5-三磷酸，招募含有 P 盒（PH 结构域）的效应蛋白（如 PKB/Akt）至细胞膜。PI3K 激活的通路似乎能增强巨噬细胞的增殖、生存和迁移，并通过诱导 miR21 来抑制炎症反应，靶向编码多种促炎分子的 mRNA。PLCG2 结合 CSF1R 酪氨酸 723 位磷酸化残基，水解磷脂酰胆碱产生磷酸胆碱和二酰基甘油，并通过 PKCdelta（PRKCD）促进巨噬细胞的生存和分化。GRB2:SOS1 与 CSF1R 酪氨酸 699 位磷酸化残基短暂相互作用，SOS1 促进 KRAS 的 GDP/GTP 交换，激活 RAS-RAF-ERK1/2 通路，导致巨噬细胞前体细胞的增殖。CBL 短暂结合并泛素化 CSF1R，随后被去泛素化并返回细胞质。磷酸化 CSF1R 还招募 STAT1 和 STAT3，随后被磷酸化（具体作用机制尚不完全清楚）。CSF1R 是药物靶点，如伊马替尼（reviewed in Kumari et al. 2018）。
英文描述
Transcriptional Regulation by VENTX The VENTX (also known as VENT homeobox or VENTX2) gene is a member of the homeobox family of transcription factors. The ortholog of VENTX was first described in Xenopus where it participates in BMP and Nanog signaling pathways and controls dorsoventral mesoderm patterning (Onichtchouk et al. 1996, Scerbo et al. 2012). The zebrafish ortholog of VENTX is also involved in dorsoventral patterning in the early embryo (Imai et al. 2001). Rodents lack the VENTX ortholog (Zhong and Holland 2011). VENTX is expressed in human blood cells (Moretti et al. 2001) and appears to play an important role in hematopoiesis. The role of VENTX in hematopoiesis was first suggested based on its role in mesoderm patterning in Xenopus and zebrafish (Davidson and Zon 2000). VENTX promotes cell cycle arrest and differentiation of hematopoietic stem cells and/or progenitor cells (Wu, Gao, Ke, Giese and Zhu 2011, Wu et al. 2014). Ventx suppression leads to expansion of hematopoietic stem cells and multi-progenitor cells (Gao et, J. Biol.Chem, 2012). VENTX induces transcription of cell cycle inhibitors TP53 (p53) and p16INK4A and activates tumor suppressor pathways regulated by TP53 and p16INK4A (Wu, Gao, Ke, Hager et al. 2011), as well as macrophage colony stimulating factor receptor (CSF1R) (Wu, Gao, Ke, Giese and Zhu 2011) and inhibits transcription of cyclin D1 (CCND1) (Gao et al. 2010) and Interleukin-6 (IL6) (Wu et al. 2014). Chromatin immunoprecipitation showed that EGR3 transcription factor directly binds to the promoter of IL6 and IL8 genes (Baron VT et al, BJC 2015). While VENTX expression may suppress lymphocytic leukemia (Gao et al. 2010), high levels of VENTX have been reported in acute myeloid leukemia cells, with a positive effect on their proliferation (Rawat et al. 2010). Another homeobox transcription factor that regulates differentiation of hematopoietic stemm cells is DLX4 (Bon et al. 2015). Studies on colon cancer showed that VentX regulates tumor associated macrophages and reverts immune suppression in tumor microenvironment (Le et al. 2018). MEK1 is required for Xenopus Ventx2 asymmetric distribution during blastula cell division. Ventx2 inhibition by MEK1 is required for embryonic cell commitment (Scerbo et al, eLife, 2017). VENTX induces TP53-independent apoptosis in cancer cells (Gao H, Oncotarget, 2016). During Xenopus embryonic development, VENTX ortholog regulates transcription of the sox3 gene (Rogers et al. 2007) as well as the early neuronal gene zic3 (Umair et al. 2018).
所含基因
38 个基因