The small GTPase RhoH is an atypical regulator of haematopoietic cells.
The small GTPase RhoH is an atypical regulator of haematopoietic cells.
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DOI：
10.1186/1478-811x-6-6
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发表时间：
2008-09-29
期刊：
影响因子：
--
通讯作者：
Kubatzky KF
中科院分区：
文献类型：
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作者：
Fueller F;Kubatzky KF
Rho GTP酶是Ras GTP酶超家族的独特亚家族。最具特征的成员是RhoA，Rac和Cdc 42，它们调节许多不同的作用，如肌动蛋白细胞骨架重组，粘附，运动以及细胞增殖，分化和基因转录。在该家族的20个成员中，只有Rac 2和RhoH显示出仅限于造血谱系的表达。RhoH在1995年首次被发现是与转录抑制因子LAZ 3/BCL 6的融合转录物。因此，它最初被命名为翻译三四（TTF），但后来更名为RhoH，因为它与GTP酶的Ras/Rho家族关系密切。从那时起，RhoH已经被牵连在人类癌症中，因为该基因经历体细胞超突变，并且通过检测RhoH作为LAZ 3/BCL 6或人类淋巴瘤中其他基因的易位伴侣。RhoH的低表达见于毛细胞白血病和急性髓系白血病。RhoH中对GT3活性至关重要的一些氨基酸发生突变，因此该蛋白质是GT3酶缺陷型，即所谓的非典型Rho GT3。因此，已经描述了调节RhoH活性的其他机制。这些包括在mRNA水平的调节和蛋白质的独特ITAM样基序的酪氨酸磷酸化。RhoH的C末端CaaX盒主要是法尼基转移酶的靶标，但也可以被香叶基香叶基转移酶修饰。RhoH的异戊二烯化和亚细胞定位的变化可能是微调信号传导的另一个因素。目前对其信号、调节或相互作用伙伴知之甚少。最近的研究表明，RhoH负面影响小鼠造血祖细胞的增殖和归巢，大概是作为Rac 1的拮抗剂。在白细胞中，需要RhoH来保持细胞处于静止的非粘附状态，但确切的机制尚未阐明。RhoH也被认为是NFκB、PI 3激酶和Map激酶途径中的调节分子。最近一代RhoH基因敲除小鼠表现出胸腺细胞选择和胸腺和外周T细胞TCR信号传导的缺陷。然而，RhoH缺陷小鼠没有发展淋巴瘤或表现出明显的造血缺陷。
Rho GTPases are a distinct subfamily of the superfamily of Ras GTPases. The best-characterised members are RhoA, Rac and Cdc42 that regulate many diverse actions such as actin cytoskeleton reorganisation, adhesion, motility as well as cell proliferation, differentiation and gene transcription. Among the 20 members of that family, only Rac2 and RhoH show an expression restricted to the haematopoietic lineage. RhoH was first discovered in 1995 as a fusion transcript with the transcriptional repressor LAZ3/BCL6. It was therefore initially named translation three four (TTF) but later on renamed RhoH due to its close relationship to the Ras/Rho family of GTPases. Since then, RhoH has been implicated in human cancer as the gene is subject to somatic hypermutation and by the detection of RHOH as a translocation partner for LAZ3/BCL6 or other genes in human lymphomas. Underexpression of RhoH is found in hairy cell leukaemia and acute myeloid leukaemia. Some of the amino acids that are crucial for GTPase activity are mutated in RhoH so that the protein is a GTPase-deficient, so-called atypical Rho GTPase. Therefore other mechanisms of regulating RhoH activity have been described. These include regulation at the mRNA level and tyrosine phosphorylation of the protein's unique ITAM-like motif. The C-terminal CaaX box of RhoH is mainly a target for farnesyl-transferase but can also be modified by geranylgeranyl-transferase. Isoprenylation of RhoH and changes in subcellular localisation may be an additional factor to fine-tune signalling. Little is currently known about its signalling, regulation or interaction partners. Recent studies have shown that RhoH negatively influences the proliferation and homing of murine haematopoietic progenitor cells, presumably by acting as an antagonist for Rac1. In leukocytes, RhoH is needed to keep the cells in a resting, non-adhesive state, but the exact mechanism has yet to be elucidated. RhoH has also been implicated as a regulatory molecule in the NFκB, PI3 kinase and Map kinase pathways. The recent generation of RhoH knockout mice showed a defect in thymocyte selection and TCR signalling of thymic and peripheral T-cells. However, RhoH-deficient mice did not develop lymphomas or showed obvious defects in haematopoiesis.