Signaling by CSF3 (G-CSF)

CSF3 (GCSF) is a cytokine that regulates production of neutrophils and granulocytes (reviewed in Panopoulos and Watowich 2008). CSF3 circulates extracellularly as a dimer and binds to the monomeric receptor CSF3R (GCSFR) on neutrophil precursors and mature neutrophils (reviewed in Futosi et al. 2013). CSF3R possesses no catalytic activity of its own and is constitutively associated with the kinases LYN (Corey et al. 1994) and JAK1 (Nicholson et al. 1994). Upon binding the CSF3 dimer, CSF3R dimerizes, is phosphorylated, and activates JAK-STAT signaling, RAS-RAF-MEK-ERK signaling, and PI3K signaling (reviewed in Basu et al. 2002, Roberts et al. 2005, Kendricks and Bogoyevitch 2007, Touw and van de Geijn 2007).<br>After dimerization of CSF3R, JAK1 associated with CSF3R is required for phosphorylation of tyrosine residues in the cytosolic domain of CSF3R which recruit further kinases such as JAK2, SYK, HCK, and TYK2 (reviewed in Sampson et al. 2007). Phosphorylated JAK1 and JAK2 then appear to act redundantly to phosphorylate STAT proteins (STAT1, STAT3, STAT5) which dimerize and transit to the nucleus to activate gene expression.<br>CSF3 signaling also activates the RAS pathway, resulting in activation of ERK1 and ERK2 and cellular proliferation. Phosphorylated CSF3R recruits both GRB2, which can act as a scaffold for RAS guanyl exchange factors SOS and VAV, and PTPN11 (SHP2), which activates RAS by dephosphorylating tyrosine-32 of RAS (Bunda et al. 2015). Association of SOS or VAV with the phosphorylated CSF3R has not yet been shown. The pathway to activation of PI3K is uncertain but appears to proceed via GAB2 bound to CSF3R.<br>Mutations in CSF3R can occur during the course of Kostmann disease, a severe congenital neutropenia (reviewed in Zeidler and Welte 2002, Zeidler 2005, Ward 2007, Vandenberghe and Beel 2011). Somatic mutations in CSF3R, principally truncations of the C-terminal region, are involved in the pathogenesis of severe congenital neutropenia and are associated with progression to acute myeloid leukemia (Dong et al. 1995, reviewed in Ward 2007, Beekman and Touw 2010, Xing and Zhao 2016). Loss or mutation of the C-terminal region of CSF3R interferes with inhibition and turnover of the receptor. Mutation of Thr-618 to Ile-618 in CSF3R causes spontaneous dimerization and consequent autoactivation leading to CSF3-independent signaling and chronic neutrophilic leukemia (Maxson et al. 2013).

CSF3（GCSF）是一种调节中性粒细胞和粒细胞产生的细胞因子（详见Panopoulos和Watowich，2008年的综述）。CSF3以二聚体的形式在细胞外循环，并与中性粒细胞前体和成熟中性粒细胞上的单聚体受体CSF3R（GCSFR）结合（详见Futosi等人，2013年的综述）。CSF3R本身不具备催化活性，并持续与激酶LYN（Corey等人，1994年）和JAK1（Nicholson等人，1994年）结合。CSF3二聚体结合后，CSF3R二聚化、磷酸化，并激活JAK-STAT信号通路、RAS-RAF-MEK-ERK信号通路和PI3K信号通路（详见Basu等人，2002年；Roberts等人，2005年；Kendricks和Bogoyevitch，2007年；Touw和van de Geijn，2007年的综述）。在CSF3R二聚化后，与CSF3R结合的JAK1负责磷酸化CSF3R细胞质结构域中的酪氨酸残基，进而募集进一步的激酶，如JAK2、SYK、HCK和TYK2（详见Sampson等人，2007年的综述）。磷酸化的JAK1和JAK2似乎以冗余的方式磷酸化STAT蛋白（STAT1、STAT3、STAT5），这些蛋白二聚化并转移到细胞核中，从而激活基因表达。CSF3信号通路还激活RAS通路，导致ERK1和ERK2的激活以及细胞增殖。磷酸化的CSF3R募集GRB2，GRB2可以作为RAS鸟苷交换因子SOS和VAV的支架，并募集PTPN11（SHP2），PTPN11通过去磷酸化RAS的酪氨酸-32位激活RAS（详见Bunda等人，2015年的研究）。SOS或VAV与磷酸化的CSF3R的关联尚未得到证实。PI3K激活的通路尚不明确，但似乎是通过与CSF3R结合的GAB2进行的。CSF3R突变可能在Kostmann病（一种严重的先天性中性粒细胞减少症）的病程中发生（详见Zeidler和Welte，2002年；Zeidler，2005年；Ward，2007年；Vandenberghe和Beel，2011年的综述）。CSF3R的体细胞突变，主要是C端区域的截断，与严重先天性中性粒细胞减少症的发病机制有关，并与其发展为急性髓系白血病相关（详见Dong等人，1995年的研究；Ward，2007年；Beekman和Touw，2010年；Xing和Zhao，2016年的综述）。CSF3R的C端区域丢失或突变干扰了受体的抑制和更新。CSF3R中Thr-618到Ile-618的突变导致自发的二聚化和随后的自激活，进而导致CSF3非依赖性信号传导和慢性中性粒细胞白血病（详见Maxson等人，2013年的研究）。