Gene interactions and pathways from curated databases and text-mining
Biochim Biophys Acta 2013, PMID: 23348097

XLID CUL4B mutants are defective in promoting TSC2 degradation and positively regulating mTOR signaling in neocortical neurons.

Wang, Hung-Li; Chang, Ning-Chun; Weng, Yi-Hsin; Yeh, Tu-Hsueh

Truncating or missense mutation of cullin 4B (CUL4B) is one of the most prevalent causes underlying X-linked intellectual disability (XLID). CUL4B-RING E3 ubiquitin ligase promotes ubiquitination and degradation of various proteins. Consistent with previous studies, overexpression of wild-type CUL4B in 293 cells enhanced ubiquitylation and degradation of TSC2 or cyclin E. The present study shows that XLID mutant (R388X), (R572C) or (V745A) CULB failed to promote ubiquitination and degradation of TSC2 or cyclin E. Adenoviruses-mediated expression of wild-type CUL4B decreased protein level of TSC2 or cyclin E in cultured neocortical neurons of frontal lobe. Furthermore, shRNA-mediated CUL4B knockdown caused an upregulation of TSC2 or cyclin E. XLID mutant (R388X), (R572C) or (V745A) CUL4B did not downregulate protein expression of TSC2 or cyclin E in neocortical neurons. By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex. Consistent with this hypothesis, CUL4B knockdown-induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR(Ser2448) and a reduced expression of active phospho-p70S6K(Thr389) and phospho-4E-BP1(Thr37/46), two main substrates of mTOR-mediated phosphorylation. Wild-type CUL4B also increased protein level of active phospho-mTOR(Ser2448), phospho-p70S6K(Thr389) or phospho-4E-BP1(Thr37/46). XLID CUL4B mutants did not affect protein level of active phospho-mTOR(Ser2448), phospho-p70S6K(Thr389) or phospho-4E-BP1(Thr37/46). Our results suggest that XLID CUL4B mutants are defective in promoting TSC2 degradation and positively regulating mTOR signaling in neocortical neurons.

Diseases/Pathways annotated by Medline MESH: Genetic Diseases, X-Linked, Intellectual Disability
Document information provided by NCBI PubMed

Text Mining Data

mTOR → CUL4B: " By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex "

mTOR → CUL4B: " By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex "

CUL4B — TSC2: " By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex "

CUL4B — TSC2: " By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex "

mTOR — TSC2: " By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex "

phospho-4E-BP1 ⊣ TSC2: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-4E-BP1 ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-4E-BP1 ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-mTOR ⊣ TSC2: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-mTOR ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-mTOR ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-p70S6K ⊣ TSC2: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-p70S6K ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-p70S6K ⊣ CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

TSC2 → CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

TSC2 → CUL4B: " Consistent with this hypothesis, CUL4B knockdown induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation "

phospho-4E-BP1 → CUL4B: " Wild-type CUL4B also increased protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

phospho-mTOR → CUL4B: " Wild-type CUL4B also increased protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

phospho-p70S6K → CUL4B: " Wild-type CUL4B also increased protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

phospho-4E-BP1 — CUL4B: " XLID CUL4B mutants did not affect protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

phospho-mTOR — CUL4B: " XLID CUL4B mutants did not affect protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

phospho-p70S6K — CUL4B: " XLID CUL4B mutants did not affect protein level of active phospho-mTOR ( Ser2448 ), phospho-p70S6K ( Thr389 ) or phospho-4E-BP1 ( Thr37/46 ) "

Manually curated Databases

No curated data.