Редактирование: CUL3

Cullin-3 (CUL-3) [KIAA0617]

==Publications==

{{medline-entry
|title=[[KLHL22]] activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29769719
|abstract=The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental cues, including amino acids . Deregulation of mTORC1 has been linked with metabolic diseases, cancer and ageing . In response to amino acids, mTORC1 is recruited by the Rag GTPases to the lysosome, its site of activation . The GATOR1 complex, consisting of [[DEPDC5]], [[NPRL3]] and [[NPRL2]], displays GAP activity to inactivate Rag GTPases under amino-acid-deficient conditions   . However, it is unclear how the inhibitory function of GATOR1 is released upon amino acid stimulation. Here we find that in response to amino acids, the [[CUL3]]-[[KLHL22]] E3 ubiquitin ligase promotes K48-linked polyubiquitination and degradation of [[DEPDC5]], an essential subunit of GATOR1. [[KLHL22]] plays a conserved role to mediate the activation of mTORC1 and downstream events in mammals and nematodes. Depletion of MEL-26, the Caenorhabditis elegans orthologue of [[KLHL22]], extends worm lifespan. Moreover, [[KLHL22]] levels are elevated in tumours of breast cancer patients, whereas [[DEPDC5]] levels are correspondingly reduced. Depletion of [[KLHL22]] in breast cancer cells suppresses tumour growth in nude mice. Therefore, pharmacological interventions targeting [[KLHL22]] may have therapeutic potential for the treatment of breast cancer and age-related diseases.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Autophagy
* Breast Neoplasms
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Carcinogenesis
* Cell Line
* Cell Proliferation
* Cullin Proteins
* Female
* GTPase-Activating Proteins
* Humans
* Longevity
* Mechanistic Target of Rapamycin Complex 1
* Mice
* Mice, Nude
* Multiprotein Complexes
* Oncogenes
* Proteolysis
* Repressor Proteins
* Signal Transduction
* Tumor Suppressor Proteins
* Ubiquitin-Protein Ligases
* Ubiquitination

|full-text-url=https://sci-hub.do/10.1038/s41586-018-0128-9
}}