IndraLab

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Mutated KRAS increases the amount of JOSD2. 6 / 6
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"As shown in Fig. 4q, KRAS mutants significantly upregulated JOSD2 levels, but failed to pose similar effects in CHIP-depleted cells, indicating that KRAS mutants upregulated JOSD2 relying on CHIP.Given that JOSD2 functions as a DUB, we further investigate whether JOSD2 exhibits auto-DUB activity."
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"Mechanically, KRAS mutants positively regulated JOSD2 protein levels and stability in a CHIP-dependent manner and then restrained JOSD2 proteasomal degradation at K48, K142, and K181."
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"However, despite the activated state of YAP/TAZ, depletion of JOSD2 still shows more robust anti-tumor effects in KRAS-mutant xenografts compared to the wild-type counterparts, further demonstrating that the growth-inhibitory effect of JOSD2 knockdown depends, at least partially, on the degradation of mutant KRAS.Given that KRAS mutants upregulated JOSD2 levels relying on CHIP, whether CHIP overexpression plays a similar role as JOSD2 shRNA?"
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"Based on this understanding, we propose that KRAS mutants specifically upregulate JOSD2 levels by inhibiting the MEK5-ERK5 cascade, which mediates the promotion of CHIP activity ."
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"Correspondingly, depletion of KRAS mutants dramatically downregulated JOSD2 levels (Fig. 4c), indicating KRAS mutants positively regulated JOSD2 levels."
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"More importantly, KRAS mutants have been reported to suppress E3 enzymatic activity of CHIP , we next attempted to demonstrate whether KRAS mutants upregulating JOSD2 levels depend on CHIP."
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