Regulation of c-Raf Stability through the CTLH Complex

McTavish, Christina J; Bérubé-Janzen, Wesley; Wang, Xu; Maitland, Matthew E. R.; Salemi, Louisa M.; Hess, David A.; Schild-Poulter, Caroline

doi:10.3390/ijms20040934

Cited by 19 publications

(34 citation statements)

References 48 publications

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“…The WD40 repeats of WDR26 are required for the binding and ubiquitination of HBP1, but GID4 is not, providing important evidence that the human complex can engage substrates independent of GID4 [ 20 ]. Increased cell growth in contrast to what was reported in Lampert et al, 2018 [ 16 ], was observed in RMND5A knockout HEK293 cells and RanBP9-depleted HEK293 cells and mouse embryonic fibroblasts [ 132 , 133 ]. Furthermore, the downregulation of RanBP9 promoted tumour formation in a mouse xenograft model [ 133 ].…”

Section: Functions and Ubiquitination Targets Of The Ctlh Complex Fro...mentioning

confidence: 88%

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Maitland

Lajoie

Shaw

et al. 2022

IJMS

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Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called the glucose-induced degradation deficient (GID) complex, is a multi-subunit E3 ligase complex highly conserved from Saccharomyces cerevisiae to humans, with roles in fundamental pathways controlling homeostasis and development in several species. However, we are only beginning to understand its mechanistic basis. Here, we review the literature of the CTLH complex from all organisms and place previous findings on individual subunits into context with recent breakthroughs on its structure and function.

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Section: Functions and Ubiquitination Targets Of The Ctlh Complex Fro...mentioning

confidence: 88%

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Maitland

Lajoie

Shaw

et al. 2022

IJMS

Self Cite

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“…Qiao et al (46) employed cryoelectron microscopy and other methods to characterize the entire GID Ub ligase, revealing its overall shape and also, in particular, specific interactions between its N-recognin subunit GID4 and the rest of GID. In mammals, the GID Ub ligase (it is also called CTLH) functions in primary cilia, in cell proliferation, and in other processes (96,(102)(103)(104)(105)(106)(107)(108)(109)(110).…”

Section: Significancementioning

confidence: 99%

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

Cheng

Chen

Melnykov³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with aKdof 16 μM, whereas the otherwise identical Nt-Pro–bearing sequence PGLW binds to GID4 more tightly, with aKdof 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeastSaccharomyces cerevisiaecan target an Nt-IGLW–bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.

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“…Specific kinases comprise 3 contributors in higher vertebrates, A-Raf, B-Raf and C-Raf or Raf-l, which play a vital role in regulating cellular growth, differentiation and apoptosis 36 . They lie on the apex of a quite conserved protein kinase module which relays extracellular indicators to the nucleus 37 . In these modules Raf kinases phosphorylates and turns on MEK-112 which in turn phosphorylates and activates ERK-112 38 .…”

Section: Map Kinasementioning

confidence: 99%

Monitoring Cellular Immune Responses in Cancer Therapy

Chanda¹,

Muktha²,

Manaswini³

et al. 2020

Int J Pharma Bio Sci

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Cytokines are probably the most important biologically active group of molecules to be identified since the discovery of the classical endocrine hormones. Progress with the identification of new cytokine molecules is particularly fast approaching and now it is evident that cytokines are involved, at least to some extent, in most if not all physiological processes. According to the National Cancer Institute, USA, "Cancer" is a term used for sicknesses in which atypical cells divide without manage and are capable of invading different cells. Cancer is typically characterized as a heightened proliferation of cells. Cancer arises from the dysfunction of many critical cell checkpoints. By utilizing the knowledge of unique or overexpressed cell-surface antigens or receptors on tumour cells as targets, a new form of cancer therapy has evolved over the last two decades. In particular, a variety of receptors for cellular growth factors and cytokines are overexpressed on tumour cells, which may serve as targets for cancer therapy. Previous studies reported that neutralizing monoclonal antibodies either alone or attached with radionuclide or antisense oligonucleotides to some of these receptors can selectively inhibit the growth of tumour cells by evoking host immune responses. For direct tumour cell killing, antibodies or ligands have been chemically conjugated or genetically fused to plant or bacterial toxins. Current medicinal treatments for cancer, including chemotherapy consider cytokine therapy as adjuvant therapy. Being a novel therapeutic approach, cytokine therapy has proved successful in treating patients having advanced malignancies. It manipulates the immune response generating immune effector cells for eradicating solid tumours. Only after the conventional therapies like chemotherapy, surgery etc having been performed is cytokine therapy administered. Clinical trials have already been performed for the administration of TNF-α, INFα, IL-2, IL-12. Some clinical trials have given positive results in the form of partial or complete tumour regression. This has raised hope for selecting a suitable cytokine or its combination, its dose level for treating advanced malignancies.

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Regulation of c-Raf Stability through the CTLH Complex

Cited by 19 publications

References 48 publications

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

Monitoring Cellular Immune Responses in Cancer Therapy

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