CSF3（粒细胞集落刺激因子）信号传导
中文名称
通路描述
CSF3（G-CSF）是一种调节中性粒细胞和粒细胞产生的细胞因子。CSF3在细胞外以二聚体形式循环，并与中性粒细胞前体及成熟中性粒细胞上的单体受体CSF3R（GCSFR）结合。CSF3R本身无催化活性，常与激酶LYN和JAK1结合。当结合CSF3二聚体时，CSF3R二聚化、磷酸化并激活JAK-STAT、RAS-RAF-MEK-ERK及PI3K信号通路。JAK1与CSF3R结合后，磷酸化CSF3R胞质域上的酪氨酸残基，招募JAK2、SYK、HCK和TYK2等激酶。磷酸化的JAK1和JAK2协同磷酸化STAT蛋白（STAT1、STAT3、STAT5），使其二聚化并转运至细胞核以激活基因表达。CSF3信号还激活RAS通路，导致ERK1和ERK2激活及细胞增殖。磷酸化的CSF3R招募GRB2（可作为RAS鸟苷酸交换因子SOS和VAV的支架）和PTPN11（SHP2），后者通过脱磷酸化RAS的酪氨酸32位点激活RAS。SOS或VAV与磷酸化CSF3R的结合尚未证实。PI3K激活途径尚不确定，但似乎通过GAB2与CSF3R结合进行。CSF3R突变可发生在Kostmann病过程中，这是一种严重的先天性中性粒细胞减少症。CSF3R的体细胞突变，主要是C端区域的截短，与严重先天性中性粒细胞减少症的发病机制相关，并与向急性髓系白血病进展相关。CSF3R C端区域的缺失或突变干扰受体的抑制和周转。CSF3R Thr-618突变为Ile-618会导致自发二聚化和随后的自激活，导致无CSF3信号传导的慢性中性粒细胞白血病。
英文描述
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009).
The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003).
SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000).
MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).
JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).
The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003).
SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000).
MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).
JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).
所含基因
36 个基因