The Src Homology 2 (SH2) Domain of SH2-containing Inositol Phosphatase (SHIP) Is Essential for Tyrosine Phosphorylation of SHIP, Its Association with Shc, and Its Induction of Apoptosis*
The Src Homology 2 (SH2) Domain of SH2-containing Inositol Phosphatase (SHIP) Is Essential for Tyrosine Phosphorylation of SHIP, Its Association with Shc, and Its Induction of Apoptosis*
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含 SH2 的肌醇磷酸酶 (SHIP) 的 Src 同源 2 (SH2) 结构域对于 SHIP 的酪氨酸磷酸化、其与 Shc 的关联以及诱导细胞凋亡至关重要*
DOI：
10.1074/jbc.272.14.8983
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
G. Krystal
中科院分区：
文献类型：
--
作者：
Ling Liu;J. Damen;M. Hughes;I. Babic;F. Jirik;G. Krystal
在这项研究中，我们已经调查的Src同源2域（SH 2）的145 kDa的5-磷酸酶，SH 2-含肌醇磷酸酶（SHIP），在三个属性，已与此蛋白质细胞因子刺激后发挥的作用：其关联与Shc，其酪氨酸磷酸化，其抑制造血细胞生长。使用该SH 2结构域的体外研究表明，它能够以约290 nM的KD直接结合Shc的Tyr（P）317基序，与其他特异性SH 2/Tyr（P）相互作用保持一致。体内分析显示SHIP的SH 2和NPXpY基序分别与Shc的Tyr（P）317和磷酸酪氨酸结合（PTB）结构域共同作用，以确保高亲和力的SHIP·Shc复合物。在小鼠造血细胞系DA-ER中表达编码血凝素标记的野生型和SH 2失活形式的SHIP的cDNA揭示，野生型SHIP在白细胞介素-3刺激后变得酪氨酸磷酸化并与Shc相关，正如预期的那样，但SH 2失活的SHIP两者都没有。此外，虽然亲本DA-ER细胞和表达这些不同SHIP构建体的细胞的生长速率相同，但表达野生型SHIP的细胞通过程序性细胞死亡比亲本细胞快得多。另一方面，表达SH 2失活SHIP的细胞显示对细胞凋亡的影响减少或没有影响。这些结果表明，SHIP的SH 2结构域不仅是细胞因子刺激后SHIP和Shc结合的酪氨酸磷酸化所必需的，而且也是其诱导细胞凋亡所必需的。
In this study we have investigated the role that the Src homology 2 domain (SH2) of the 145-kDa 5-phosphatase, SH2-containing inositol phosphatase (SHIP), plays in three of the properties that have been associated with this protein following cytokine stimulation: its association with Shc, its tyrosine phosphorylation, and its inhibition of hemopoietic cell growth. In vitro studies using this SH2 domain revealed that it was capable of binding directly to the Tyr(P)317 motif of Shc with a KD of approximately 290 nM, in keeping with other specific SH2/Tyr(P) interactions. In vivo analysis revealed the SH2 and NPXpY motifs of SHIP acted together, with the Tyr(P)317 and phosphotyrosine binding (PTB) domains of Shc, respectively, to ensure a high affinity SHIP·Shc complex. Expression of cDNAs encoding hemagglutinin-tagged wild type and SH2-inactivated forms of SHIP in the murine hemopoietic cell line DA-ER revealed that wild type SHIP becomes both tyrosine-phosphorylated and associated with Shc following interleukin-3 stimulation, as expected, but the SH2-inactivated SHIPs do neither. Moreover, while the growth rates of parental DA-ER cells and cells expressing these various SHIP constructs are identical, the wild type SHIP-expressing cells die, via programmed cell death, far more rapidly than parental cells. Cells expressing SH2-inactivated SHIPs, on the other hand, show either a reduced or no effect on apoptosis. These results suggest that the SH2 domain of SHIP is required not only for the tyrosine phosphorylation of SHIP and Shc association following cytokine stimulation but also for its induction of apoptosis.
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