Chen Yuhong, Yu Mei, Podd Andrew, Wen Renren, Chrzanowska-Wodnicka Magdalena, White Gilbert C, Wang Demin
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
Blood. 2008 May 1;111(9):4627-36. doi: 10.1182/blood-2007-12-128140. Epub 2008 Mar 4.
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.
B细胞的发育由复杂的信号网络精心调控。Rap1是小GTP结合蛋白Ras超家族的成员，有Rap1a和Rap1b两种异构体。尽管有研究表明Rap1在多种细胞过程中发挥重要作用，但尚无直接证据证明Rap1在B细胞生物学中的作用。在本研究中，我们发现Rap1b是B细胞中Rap1的主要异构体。我们发现，小鼠中Rap1b的缺失对B细胞的早期发育几乎没有影响，但显著减少了脾脏边缘区（MZ）B细胞以及外周和黏膜淋巴结中的成熟B细胞。Rap1b缺陷型B细胞在体内和体外均表现出正常的存活和增殖能力。然而，Rap1b缺陷型B细胞在体外的黏附能力受损且趋化性降低，在体内归巢至淋巴结的能力也减弱。此外，我们发现Rap1b的缺失对LPS、BCR或SDF-1诱导的丝裂原活化蛋白激酶和AKT的激活没有显著影响，但明显损害了SDF-1介导的Pyk-2的激活，Pyk-2是SDF-1介导的B细胞迁移的关键调节因子。因此，我们发现了Rap1b在成熟B细胞转运和MZ B细胞发育中的关键且独特的作用。
