The Ras-related Protein Rheb Is Farnesylated and Antagonizes Ras Signaling and Transformation*
The Ras-related Protein Rheb Is Farnesylated and Antagonizes Ras Signaling and Transformation*
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DOI：
10.1074/jbc.272.16.10608
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发表时间：
1997-04
期刊：
影响因子：
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通讯作者：
G. Clark;M. Kinch;K. Rogers-Graham;S. Sebti;A. Hamilton;C. Der
中科院分区：
文献类型：
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作者：
G. Clark;M. Kinch;K. Rogers-Graham;S. Sebti;A. Hamilton;C. Der
目前，对Ras相关蛋白Rheb的功能一无所知。由于Rheb与Ras和KRev-1/Rap 1A的核心效应结构域具有显著的序列同一性，因此它可能与这两种结构相关但功能不同的小GTP酶具有功能相似性。此外，由于与Ras类似，Rheb以可能发出法尼基化信号的COOH末端终止，因此它可能是阻断Ras加工和功能的法尼基转移酶抑制剂的靶标。为了将Rheb的功能与Ras和KRev-1的功能进行比较，我们将突变引入Rheb中，这些突变产生Ras和Ras相关蛋白的组成型活性或显性阴性形式，并分别命名为Rheb（64 L）和Rheb（20 N）。野生型或突变型Rheb的表达没有改变NIH 3 T3细胞的形态或生长特性。因此，异常的Rheb功能不同于Ras的功能，并且不能引起细胞转化。相反，与KRev-1类似，Rheb的共表达拮抗致癌Ras转化和信号传导。体外和体内分析表明，像Ras，Rheb蛋白是法尼基化的，对法尼基转移酶抑制敏感。因此，法尼基转移酶抑制剂治疗可能抑制Rheb功能，因此可能有助于这些抑制剂损害Ras转化的能力。
Presently, nothing is known about the function of the Ras-related protein Rheb. Since Rheb shares significant sequence identity with the core effector domains of Ras and KRev-1/Rap1A, it may share functional similarities with these two structurally related, yet functionally distinct, small GTPases. Furthermore, since like Ras, Rheb terminates with a COOH terminus that is likely to signal for farnesylation, it may be a target for the farnesyltransferase inhibitors that block Ras processing and function. To compare Rheb function with those of Ras and KRev-1, we introduced mutations into Rheb that generate constitutively active or dominant negative forms of Ras and Ras-related proteins and were designated Rheb(64L) and Rheb(20N), respectively. Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells. Thus, aberrant Rheb function is distinct from that of Ras and fails to cause cellular transformation. Instead, similar to KRev-1, co-expression of Rheb antagonized oncogenic Ras transformation and signaling. In vitro and in vivo analyses showed that like Ras, Rheb proteins are farnesylated and are sensitive to farnesyltransferase inhibition. Thus, it is possible that Rheb function may be inhibited by farnesyltransferase inhibitors treatment and, consequently, may contribute to the ability of these inhibitors to impair Ras transformation.