Ksionda Olga, Limnander Andre, Roose Jeroen P
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Front Biol (Beijing). 2013 Oct 1;8(5):508-532. doi: 10.1007/s11515-013-1276-9.
RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through -4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.
RasGRP蛋白作为鸟嘌呤核苷酸交换因子（GEF），是Ras及其他相关小GTP酶的激活剂。在脊椎动物中，已发现四个RasGRP家族成员。RasGRP-1至-4具有许多结构域，但不同家族成员之间也存在细微差异。SOS RasGEF在全身广泛表达，而RasGRP蛋白则以不同模式表达，例如在造血系统的不同细胞和大脑中。由于RasGRP在这些细胞中的主要表达谱以及基因缺陷小鼠的免疫表型，大多数研究都集中在RasGRP蛋白在免疫细胞类型发育和功能中的作用。然而，最近的研究表明，RasGRP在肿瘤发生中也起着重要作用。例如皮肤癌和血液系统癌症，还有实体恶性肿瘤，如黑色素瘤或前列腺癌。这些新研究提出了许多与RasGRP驱动的肿瘤发生分子机制相关的新问题且尚无答案，例如RasGRP似乎对其作出反应的新受体系统，以及在这些癌症中似乎受到干扰的RasGRP表达调控机制。在这里，我们将综述淋巴细胞中RasGRP生物学的一些已知方面，并讨论RasGRP Ras交换因子在各种生长因子受体下游的肿瘤发生中起作用这一令人兴奋的新观点。
