A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development
A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development
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DOI：
10.1182/blood-2007-12-128140
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Wang, Demin
中科院分区：
文献类型：
--
作者：
Chen, Yuhong;Yu, Mei;Wang, Demin
B细胞的发育是由复杂的信号网络协调的。Rap 1是小GTP结合蛋白Ras超家族的成员，有两种亚型，Rap 1a和Rap 1b。虽然Rap 1已被认为在各种细胞过程中发挥重要作用，但没有直接证据表明Rap 1在B细胞生物学中的作用。在本研究中，我们发现Rap 1 B是Rap 1在B细胞中的优势亚型。我们发现小鼠Rap 1 B缺乏几乎不影响B细胞的早期发育，但显著减少脾脏中的边缘区（MZ）B细胞和外周和粘膜淋巴结中的成熟B细胞。Rap 1b缺陷型B细胞在体内和体外均能正常存活和增殖。然而，Rap 1b缺陷的B细胞在体外粘附受损，趋化性降低，体内归巢淋巴结减少。此外，我们发现Rap 1b缺陷对LPS、BCR或SDF-1诱导的丝裂原活化蛋白激酶和AKT的活化没有显著影响，但明显损害了SDF-1介导的Pyk-2的活化，Pyk-2是SDF-1介导的B细胞迁移的关键调节因子。因此，我们已经发现Rap 1 B在成熟B细胞运输和MZ B细胞发育中的关键和独特的作用。
B-cell development is orchestrated by complex signaling networks. Rap1 is a member of the Ras superfamily of small GTP-binding proteins and has 2 isoforms, Rap1a and Rap1b. Although Rap1 has been suggested to have an important role in a variety of cellular processes, no direct evidence demonstrates a role for Rap1 in B-cell biology. In this study, we found that Rap1b was the dominant isoform of Rap1 in B cells. We discovered that Rap1b deficiency in mice barely affected early development of B cells but markedly reduced marginal zone (MZ) B cells in the spleen and mature B cells in peripheral and mucosal lymph nodes. Rap1b-deficient B cells displayed normal survival and proliferation in vivo and in vitro. However, Rap1b-deficient B cells had impaired adhesion and reduced chemotaxis in vitro, and lessened homing to lymph nodes in vivo. Furthermore, we found that Rap1b deficiency had no marked effect on LPS-, BCR-, or SDF-1-induced activation of mitogen-activated protein kinases and AKT but clearly impaired SDF-1-mediated activation of Pyk-2, a key regulator of SDF-1-mediated B-cell migration. Thus, we have discovered a critical and distinct role of Rap1b in mature B-cell trafficking and development of MZ B cells.