Functional analysis of an atypical nuclear small GTPase in the oncogenic signal

kappaB-Ras是一种核胞质GTPase，主要以gtp结合形式存在，无刺激条件，其细胞定位受其结合的鸟嘌呤核苷酸调节。在这里，我们发现kappaB-Ras对于Ras （G12V）诱导的肿瘤发生至关重要，尽管kappaB-Ras本身缺乏致癌活性。为了阐明kappaB-Ras参与Ras （G12V）致肿瘤发生的机制，我们纯化了包括kappaB-Ras2在内的蛋白复合物，并鉴定了新的kappaB-Ras相互作用蛋白TRB3和DDB1。TRB3对Ras （G12V）表现出抑瘤活性。此外，TRB3诱导kappaB-Ras的sumo化，这似乎导致Ras （G12V）诱导的转化受到抑制。这些观察结果表明，kappaB-Ras在致癌Ras诱导的肿瘤发生中起着关键作用，这很可能是由新型肿瘤抑制因子TRB3通过对kappaB-Ras的sumo化来调节的。

kappaB-Ras is a nuclear-cytoplasmic GTPase that mainly present as GTP-bound form with no stimulating conditions, and its cellular localization is regulated by its bound guanine nucleotides. Here, we found that kappaB-Ras is essential for Ras (G12V)-induced tumorigenesis, although kappaB-Ras itself lacks the oncogenic activities. To clarify the mechanism, by which kappaB-Ras is involved in Ras (G12V)-caused tumorigenesis, we purified the protein complexes including kappaB-Ras2, and identified novel interacting proteins of kappaB-Ras, such as TRB3 and DDB1. TRB3 exhibited the tumor suppressive activity against Ras (G12V). Furthermore, TRB3 induced SUMOylation of kappaB-Ras, and this seems to cause the inhibition of Ras (G12V)-induced transformation. These observations suggest that kappaB-Ras harbors the critical roles in tumorigenesis induced by oncogenic Ras, and this is most likely to be regulated by novel tumor suppressor TRB3 through the SUMOylation of kappaB-Ras.