The human minor histocompatibility antigen 1 is a RhoGAP.
The human minor histocompatibility antigen 1 is a RhoGAP.
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DOI：
10.1371/journal.pone.0073962
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hordijk PL
中科院分区：
文献类型：
--
作者：
de Kreuk BJ;Schaefer A;Anthony EC;Tol S;Fernandez-Borja M;Geerts D;Pool J;Hambach L;Goulmy E;Hordijk PL
人类次要组织相容性抗原HMHA-1是异体干细胞移植治疗白血病和实体瘤后免疫反应的主要靶点。由于其在造血细胞和许多实体肿瘤中的表达受限，对其细胞功能提出了疑问。对编码HMHA1蛋白的HMHA1的序列分析显示，存在一个可能的c端RhoGTPase激活蛋白（GAP）结构域和一个n端BAR结构域。rho家族gtpase，包括Rac1， Cdc42和RhoA是肌动蛋白细胞骨架的关键调节因子，并控制细胞的扩散和迁移。RhoGTPase活性受到严格控制，因为异常信号可能导致包括炎症和癌症在内的病理。鸟嘌呤核苷酸交换因子（gef）介导GDP交换GTP导致RhoGTPase激活，而gap催化活性RhoGTPase的低内在GTPase活性，导致失活。本文将HMHA1蛋白鉴定为一种新的RhoGAP。我们发现HMHA1构建体缺乏n端区域，负向调节肌动蛋白细胞骨架和细胞扩散。此外，我们发现HMHA1在体外和体内调节RhoGTPase活性。最后，我们证明了HMHA1 n端BAR结构域具有自抑制性，因为HMHA1突变体缺乏该区域，而不是全长HMHA1，对RhoGTPases表现出GAP活性。综上所述，本研究表明HMHA1作为RhoGAP调控GTPase活性、细胞骨架重塑和细胞扩散，在正常造血细胞和癌细胞中具有重要功能。
The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells.
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DOI：
10.1016/j.biocel.2007.07.011
发表时间：
2007-01-01
影响因子：
4
作者：
Guarino, Marcello
通讯作者：
Guarino, Marcello
影响因子：
--
作者：
de Kreuk BJ;Hordijk PL
通讯作者：
Hordijk PL
DOI：
10.1084/jem.20011838
发表时间：
2002-08-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Klein CA;Wilke M;Pool J;Vermeulen C;Blokland E;Burghart E;Krostina S;Wendler N;Passlick B;Riethmüeller G;Goulmy E
通讯作者：
Goulmy E
影响因子：
4
作者：
Meller, Julia;Vidali, Luis;Schwartz, Martin Alexander
通讯作者：
Schwartz, Martin Alexander
影响因子：
14.8
作者：
Kelley, Lawrence A.;Sternberg, Michael J. E.
通讯作者：
Sternberg, Michael J. E.