Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment
Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment
复制标题
DOI：
10.1073/pnas.0703354104
复制
发表时间：
2007-06-05
影响因子：
11.1
通讯作者：
Cooper, Max D.
中科院分区：
文献类型：
--
作者：
Haga, Christopher L.;Ehrhardt, Goetz R. A.;Cooper, Max D.
B细胞上的Fc受体样蛋白5（FCRL 5）在其胞浆区具有基于免疫受体酪氨酸的激活基序（ITAM）样序列和两个基于免疫受体酪氨酸的抑制基序（ITIM）。为了评估其信号传导潜力，我们在缺乏内源性Fc受体的B细胞系中表达由FCRL 5的胞质区和IgG Fc受体Fc γ RIIB的细胞外和跨膜区组成的嵌合分子的构建体。这种融合蛋白与B细胞受体（BCR）的共连接抑制了BCR介导的钙动员、细胞内酪氨酸磷酸化和Erk激酶活化。我们的突变分析表明，而酪氨酸在抑制和激活基序连接后磷酸化，只有那些在ITIM影响BCR介导的信号。这种FCRL 5抑制作用是通过含SI-12的蛋白酪氨酸磷酸酶SHP-1的双重ITIM募集介导的，SHP-1进而使BCR IG α/IG β异二聚体中基于ITAM的酪氨酸去磷酸化。FCRL 5对BCR信号传导的抑制作用对于原代B细胞同样是可证实的。虽然其配体目前是未知的，我们的结论是，FCRL 5的功能潜力，作为一个抑制性辅助受体对成熟的B细胞在人类。
The Fc receptor-like protein 5 (FCRL5) on B cells has both an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence and two consensus immumoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor Fc gamma RIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SI-12-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Ig alpha/Ig beta heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.