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JOSD2 inhibits STK11. 7 / 7
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"Collectively, these results indicated that JOSD2 negatively regulates LKB1 kinase activity in NSCLC cells through its deubiquitination activity and residues cysteine 24 and histidine 125 of JOSD2 are both important catalytic sites."
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"Notably, GST-JOSD2 significantly diminished the kinase activity of LKB1 but showed only slight effect on LKB1-3KR, suggesting that the three lysine residues responsible for K6-linked ubiquitination on LKB1 are critical in mediating JOSD2 modulation on LKB1 kinase activity (Fig. 4e)."
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"These findings not only provide a new inhibitor against DUB(s) with the potential to be developed as a candidate compound for cancer therapy, but also implicated that the pharmacological inhibition of JOSD2 by small molecular compound(s) could reactivate LKB1 by modulating its K6 linkage, thus further verified this newly-established JOSD2-LKB1 axis which was critical for NSCLC proliferation."
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"These findings are consistent with our in vitro finding that JOSD2 negatively regulates LKB1 pathway and promotes NSCLC cell growth dependent of LKB1.These results collectively provided clinical relevance that JOSD2 plays a crucial role in promoting NSCLC cell proliferation through LKB1 kinase activity inhibition."
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"JOSD2 negatively regulates LKB1/AMPK signaling."
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"Altogether, these results suggested that JOSD2 suppresses LKB1 kinase activity by removing the K6-linked polyubiquitination on lysine residues 191, 269 and 423 of LKB1."
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"Furthermore, JOSD2 overexpression attenuated the interaction of LKB1-WT, but not LKB1-3KR, with STRAD and MO25 (Fig. 4g, h, Supplementary Fig. S6f)."
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