胞质 FGFR1 融合突变体的信号传导
中文名称
通路描述
8p11 髓系增殖综合征 (EMS) 是一种侵袭性疾病，与染色体 8p11 上 FGFR1 基因上的易位事件相关。诊断时的典型症状包括嗜酸性粒细胞增多和相关的 T 细胞淋巴母细胞淋巴瘤；疾病迅速进展为急性白血病，通常是有髓系来源。目前唯一有效的治疗方法是异体干细胞移植 (综述 Jackson, 2010)。在分子水平上，EMS 似乎是由染色体 8 上的易位事件引起的，这些事件在 FGFR1 的胞内结构域与一个编码二聚化结构域的 N 端伙伴基因之间形成基因融合。由此产生的融合蛋白在配体独立的情况下二聚化，基于伙伴蛋白提供的 N 端结构域，并刺激组成型的下游 FGFR1 信号传导，而不改变受体的内在激酶活性。迄今为止，已鉴定出 11 个伙伴基因：ZMYM2、FGFR1OP、FGFR1OP2、HERVK、TRIM24、CUX1、BCR、CEP110、LRRFIP1、MYO18A 和 CPSF6，尽管并非所有基因的功能都已得到表征 (综述 Jackson, 2010, Turner and Grose, 2010; Wesche, 2011)。在检查的细胞系中，携带 FGFR1 融合基因的细胞已被证明具有转化能力，并通过抗凋亡、促生存途径支持 IL3 独立增殖 (Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999)。信号传导似乎主要通过 PLCgamma、PI3K 和 STAT 信号传导进行，MAPK 激活的贡献较小。由于融合蛋白缺乏 FRS2 结合位点，MAPK 激活的机制尚不清楚。SHC 介导的 GRB2:SOS1 招募可能是其中一种可能 (Guasch, 2001)。
英文描述
Signaling by cytosolic FGFR1 fusion mutants 8p11 myeloproliferative syndrome (EMS) is an aggressive disorder that is associated with a translocation event at the FGFR1 gene on chromosome 8p11. Typical symptoms upon diagnosis include eosinophilia and associated T-cell lymphoblastic lymphoma; the disease rapidly advances to acute leukemia, usually of myeloid lineage. At present the only effective treatment is allogenic stem cell transplantation (reviewed in Jackson, 2010).
At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011).
Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001).
At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011).
Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001).
所含基因
8 个基因