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KMID : 0578320090270010039
Molecules and Cells
2009 Volume.27 No. 1 p.39 ~ p.45
Transmembrane Helix of Novel Oncogene with Kinase-domain (NOK) Influences Its Oligomerization and Limits the Activation of RAS/MAPK Signaling
Li Ying-Hua

Wang Yin-Yin
Zhong Shan
Rong Zhi-Li
Ren Yong-Ming
Li Zhi-Yong
Zhang Shu-Ping
Chang Zhi-Jie
Liu Li
Abstract
Ligand-dependent or independent oligomerization of receptor protein tyrosine kinase (RPTK) is often an essential step for receptor activation and intracellular signaling. The novel oncogene with kinase-domain (NOK) is a unique RPTK that almost completely lacks an ectodomain, expresses intracellularly and activates constitutively. However, it is unknown whether NOK can form oligomer or what function oligomerization would have. In this study, two NOK deletion mutants were generated by either removing the ectodomain (NOK?„ECD) or including the endodomain (NOK-ICD). Co-immunoprecipitation demonstrated that the transmembrane (TM) domain of NOK was essential for its intermolecular interaction. The results further showed that NOK aggregated more closely as lower order oligomers (the dimer- and trimer-sized) than either deletion mutant did since NOK could be cross-linked by both Sulfo-EGS and formaldehyde, whereas either deletion mutant was only sensitive to Sulfo-EGS. Removing the NOK TM domain (NOK-ICD) not only markedly promoted higher order oligomerization, but also altered the subcellular localization of NOK and dramatically elevated the NOK-mediated constitutive activation of extracellular signal-regulated kinase (ERK). Moreover, NOK-ICD but not NOK or NOK?„ECD was co-localized with the upstream signaling molecule RAS on cell membrane. Thus, TM-mediated intermolecular contacting may be mainly responsible for the constitutive activation of NOK and contribute to the autoinhibitory effect on RAS/MAPK signaling.
KEYWORD
autoinhibition, NOK, oligomerization, RAS/MAPK, RPTK
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