Zwartkruis F J, Bos J L
Laboratory for Physiological Chemistry, Center for Biomedical Genetics, Utrecht University, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands.
Exp Cell Res. 1999 Nov 25;253(1):157-65. doi: 10.1006/excr.1999.4695.
The Ras-like family of small GTPases includes, among others, Ras, Rap1, R-ras, and Ral. The family is characterized by similarities in the effector domain. While the function of Ras is, at least in part, elucidated, little is known about other members of the family. Currently, much attention is focused on the small GTPase Rap1. Initially, this member was identified as a transformation suppressor protein able to revert the morphological phenotype of Ras-transformed fibroblasts. This has led to the hypothesis that Rap1 antagonizes Ras by interfering in Ras effector function. Recent analysis revealed that Rap1 is activated rapidly in response to activation of a variety of receptors. Rap1 activation is mediated by several second messengers, including calcium, diacylglycerol, and cAMP. Guanine nucleotide exchange factors (GEFs) have been identified that mediate these effects. The most interesting GEF is Epac, an exchange protein directly activated by cAMP, thus representing a novel cAMP-induced, protein kinase A-independent pathway. Furthermore, Rap1 is inactivated by specific GTPase-activating proteins (GAPs), one of which is regulated through an interaction with Galphai. While Ras and Rap1 may share some effector pathways, evidence is accumulating that Ras and Rap1 each regulate unique cellular processes in response to various extracellular ligands. For Rap1 these functions may include the control of cell morphology.
小GTP酶的Ras样家族包括Ras、Rap1、R-ras和Ral等。该家族的特点是效应器结构域具有相似性。虽然Ras的功能至少部分已被阐明,但对该家族的其他成员了解甚少。目前,小GTP酶Rap1备受关注。最初,该成员被鉴定为一种转化抑制蛋白,能够逆转Ras转化的成纤维细胞的形态表型。这导致了一种假说,即Rap1通过干扰Ras效应器功能来拮抗Ras。最近的分析表明,Rap1在多种受体激活后迅速被激活。Rap1的激活由几种第二信使介导,包括钙、二酰基甘油和cAMP。已经鉴定出介导这些效应的鸟嘌呤核苷酸交换因子(GEF)。最有趣的GEF是Epac,一种直接由cAMP激活的交换蛋白,因此代表了一种新的cAMP诱导的、不依赖蛋白激酶A的途径。此外,Rap1被特定的GTP酶激活蛋白(GAP)灭活,其中一种通过与Gαi相互作用而被调节。虽然Ras和Rap1可能共享一些效应器途径,但越来越多的证据表明,Ras和Rap1各自响应各种细胞外配体调节独特的细胞过程。对于Rap1来说,这些功能可能包括对细胞形态的控制。