Downregulation of Ras C-terminal processing by JNK inhibition.
After translation, Ras proteins undergo a series of modifications at their C-termini. This post-translational C-terminal processing is essential for Ras to become functional, but it remains unknown whether and how Ras C-terminal processing is regulated. Here we show that the C-terminal processing and subsequent plasma membrane localization of H-Ras as well as the activation of the downstream signaling pathways by H-Ras are prevented by JNK inhibition. Conversely, JNK activation by ultraviolet irradiation resulted in promotion of C-terminal processing of H-Ras. Furthermore, increased cell density promoted C-terminal processing of H-Ras most likely through an autocrine/paracrine mechanism, which was also blocked under JNK-inhibited condition. Ras C-terminal processing was sensitive to JNK inhibition in the case of H- and N-Ras but not K-Ras, and in a variety of cell types. Thus, our results suggest for the first time that Ras C-terminal processing is a regulated mechanism in which JNK is involved.
Mouri
Wataru
W
Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Tachibana
Ken
K
Tomiyama
Arata
A
Sunayama
Jun
J
Sato
Atsushi
A
Sakurada
Kaori
K
Kayama
Takamasa
T
Kitanaka
Chifumi
C
D002452:Cell Count; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D015689:Oncogene Protein p21(ras) / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014466:Ultraviolet Rays
D048670:MAP Kinase Kinase 4; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)