Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor
Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor
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DOI：
10.1182/blood.v93.1.15.401a46_15_24
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发表时间：
1999-01-01
期刊：
影响因子：
20.3
通讯作者：
Tweardy, DJ
中科院分区：
文献类型：
--
作者：
Chakraborty, A;Dyer, KF;Tweardy, DJ
Stat 3对于早期胚胎发育和由细胞因子粒细胞集落刺激因子（G-CSF）和白细胞介素-6（IL-6）诱导的骨髓分化是必需的。现已鉴定出Stat 3的两种亚型，α（p92）和β（p83），它们具有不同的转录和生物学功能。Stat 3 α和Stat 3 β的激活需要G-CSFR的远端胞质结构域，其在位置704、729、744和764处含有四个Tyr。本文报道的研究旨在确定这些酪氨酸残基中的哪些（如果有的话）参与了Stat 3 α/β募集和激活。我们发现，Stat 3 α和Stat 3 β的亲和纯化使用磷酸化肽含有Y 704和Y 744，但不是由非磷酸化肽类似物或磷酸化肽含有Y 729和Y 764。在检查这些肽去稳定和抑制活化的Stat 3的DNA结合的能力的研究中获得了互补的结果。Y 704和Y 744都有助于在含有野生型和Y-to-F突变G-CSFR构建体的M1鼠髓性白血病细胞中最佳活化Stat 3 α/β。Y 704的羧基末端+3位是Gln; YXXQ代表共有Stat 3募集和激活基序。Y 744在+3位之后是Cys（C）：YXXC，代表与Stat 3的募集和激活有关的新基序。基于已知结构的同源SH 2结构域的Stat 3的SH 2结构域的建模揭示了侧链接触+3位置的极性残基。这种取代可以通过允许结合表面与在各自的+3位置发现的Gln或Cys之间形成H-键来赋予基于Y 704和Y 744的配体的特异性。(C)1999年，美国血液学会。
Stat3 is essential for early embryonic development and for myeloid differentiation induced by the cytokines granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6). Two isoforms of Stat3 have been identified, alpha (p92) and beta (p83), which have distinct transcriptional and biological functions. Activation of both Stat3 alpha and Stat3 beta requires the distal cytoplasmic domain of the G-CSFR, which contains four Tyr at positions 704, 729, 744, and 764. The studies reported here were undertaken to determine which, if any, of these tyrosine residues participated in Stat3 alpha/beta recruitment and activation. We showed that Stat3 alpha and Stat3 beta were affinity purified using phosphopeptides containing Y704 and Y744 but not by nonphosphorylated peptide analogues or by phosphopeptides containing Y729 and Y764. Complementary results were obtained in studies examining the ability of these peptides to destabilize and inhibit DNA binding of activated Stat3. Both Y704 and Y744 contributed to optimal activation of Stat3 alpha/beta in M1 murine myeloid leukemia cells containing wild-type and Y-to-F mutant G-CSFR constructs. Carboxy-terminal to Y704 at the +3 position is Gln; YXXQ represents a consensus Stat3 recruitment and activation motif. Y744 is followed at the +3 position by Cys (C): YXXC, represents a novel motif implicated in the recruitment and activation of Stat3. Modeling of the SH2 domain of Stat3 based on homologous SH2 domains of known structure revealed polar residues whose side chains contact the +3 position. This substitution may confer specificity for the Y704- and Y744-based ligands by allowing H-bond formation between the binding surface and the Gin or Cys found at the respective +3 position. (C) 1999 by The American Society of Hematology.