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首页> 外文期刊>Molecular and Cellular Biology >Essential Role for the C-Terminal Noncatalytic Region of SHIP in FcγRIIB1-Mediated Inhibitory Signaling
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Essential Role for the C-Terminal Noncatalytic Region of SHIP in FcγRIIB1-Mediated Inhibitory Signaling

机译：SHIP的C末端非催化区在FcγRIIB1介导的抑制性信号传导中的重要作用

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The inositol phosphatase SHIP binds to the FcγRIIB1 receptor and plays a critical role in FcγRIIB1-mediated inhibition of B-cell proliferation and immunoglobulin synthesis. The molecular details of SHIP function are not fully understood. While point mutations of the signature motifs in the inositol phosphatase domain abolish SHIP's ability to inhibit calcium flux in B cells, little is known about the function of the evolutionarily conserved, putative noncatalytic regions of SHIP in vivo. In this study, through a systematic mutagenesis approach, we identified the inositol phosphatase domain of SHIP between amino acids 400 and 866. Through reconstitution of a SHIP-deficient B-cell line with wild-type and mutant forms of SHIP, we demonstrate that the catalytic domain alone is not sufficient to mediate FcγRIIB1/SHIP-dependent inhibition of B-cell receptor signaling. Expression of a truncation mutant of SHIP that has intact phosphatase activity but lacks the last 190 amino acids showed that the noncatalytic region in the C terminus is essential for inhibitory signaling. Mutation of two tyrosines within this C-terminal region, previously identified as important in binding to Shc, showed a reduced inhibition of calcium flux. However, studies with an Shc-deficient B-cell line indicated that Shc-SHIP complex formation is not required and that other proteins that bind these tyrosines may be important in FcγRIIB1/SHIP-mediated calcium inhibition. Interestingly, membrane targeting of SHIP lacking the C terminus is able to restore this inhibition, suggesting a role for the C terminus in localization or stabilization of SHIP interaction at the membrane. Taken together, these data suggest that the noncatalytic carboxyl-terminal 190 amino acids of SHIP play a critical role in SHIP function in B cells and may play a similar role in several other receptor systems where SHIP functions as a negative regulator.
机译：肌醇磷酸酶SHIP与FcγRIIB1受体结合，并在FcγRIIB1介导的B细胞增殖抑制和免疫球蛋白合成中发挥关键作用。 SHIP功能的分子细节尚未完全了解。虽然肌醇磷酸酶结构域中特征性基序的点突变消除了SHIP抑制B细胞中钙流的能力，但对于SHIP体内进化保守的假定非催化区域的功能知之甚少。在这项研究中，通过系统的诱变方法，我们确定了SHIP的肌醇磷酸酶结构域介于400和866位氨基酸之间。通过重组具有野生型和突变形式的SHIP的SHIP缺陷型B细胞系，我们证明了单独的催化结构域不足以介导FcγRIIB1/ SHIP依赖性B细胞受体信号转导的抑制。具有完整的磷酸酶活性但缺少最后190个氨基酸的SHIP截短突变体的表达表明，C末端的非催化区域对于抑制信号传导至关重要。先前已确定在与Shc的结合中起重要作用的该C端区域内的两个酪氨酸突变，降低了对钙通量的抑制。但是，对Shc缺陷型B细胞系的研究表明，不需要Shc-SHIP复合物形成，结合这些酪氨酸的其他蛋白质在FcγRIIB1/ SHIP介导的钙抑制中可能很重要。有趣的是，缺乏C末端的SHIP的膜靶向能够恢复这种抑制作用，表明C末端在SHIP相互作用在膜上的定位或稳定中起着作用。综上所述，这些数据表明，SHIP的非催化羧基末端190个氨基酸在B细胞的SHIP功能中起关键作用，并且在SHIP充当负调节剂的其他几个受体系统中也可能起类似作用。

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