The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

Schneider, Taiane; Martinez-Martinez, Arturo; Cubillos-Rojas, Mónica; Bartrons, Ramón; Ventura, Francesc; Rosa, José Luís

doi:10.18632/oncotarget.25847

Cited by 34 publications

(36 citation statements)

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“…HERC1 regulates p38 signaling. We have previously shown that the ubiquitin E3 ligase HERC1 regulates the RAF/MEK/ERK signaling pathway 8 . We wondered whether HERC1 might also regulate other MAPK pathways.…”

Section: Resultsmentioning

confidence: 99%

“…HERC1 has previously been characterized as a ubiquitin E3 ligase regulating the ERK signaling pathway in cell proliferation 8 . Here, we provide the first evidence that HERC1 also acts as a regulator of the p38 signaling pathway, and that this regulation is mediated by the MAPK kinase MKK3.…”

Section: Discussionmentioning

confidence: 99%

“…The E3 ligase HERC1 polyubiquitylates C-RAF, labeling it for proteasomal degradation 8 and thus regulating C-RAF proteostasis. C-RAF is one of the three RAF family isoforms (A, B, and C) in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Proteins containing HECT and RCC1-like domains form the HERC protein family, a subgroup of ubiquitin E3 ligases in the HECT family that regulate cellular processes such as cell cycle, cell signaling, DNA damage response, or antiviral response, and are implicated in cancer, neurological disorders, and other diseases 7 . Recently, it has been shown that the E3 ligase HERC1 regulates cell proliferation through control of the ERK signaling pathway targeting MAPK kinase kinase (MAPKKK) C-RAF for proteasomal degradation 8 . RAF (A-RAF, B-RAF, and C-RAF) serine/threonine kinases link RAS activation to activation of the MEK/ERK module.…”

mentioning

confidence: 99%

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The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling

Pedrazza

Schneider

Bartrons

et al. 2020

Sci Rep

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Protein modifications by phosphorylation or ubiquitylation have been selected throughout evolution as efficient regulatory mechanisms of cellular processes. Cell migration is a complex, highly coordinated process where these mechanisms must participate in an integrated manner to transmit signaling during migration. In this study, we show that the ubiquitin ligase HERC1 regulates the p38 signaling pathway, and that this regulation is mediated by the MAPK kinase MKK3. Moreover, we demonstrate a crosstalk between RAF and MKK3/p38 pathways where RAF acts upstream of MKK3. Mechanistically, HERC1 regulates the protein levels of C-RAF and MKK3. Thus, HERC1 ubiquitylates C-RAF, targeting it for proteasomal degradation, and RAF proteins regulate MKK3 mRNA levels. Accordingly, HERC1 knockdown induces C-RAF stabilization and activation of RAF proteins; in turn, this activation increases MKK3, which phosphorylates and activates p38. The importance of these observations is demonstrated by HERC1 regulation of cell migration through regulation of p38 signaling via a RAF-dependent mechanism. Thus, HERC1 plays an essential role as a regulator of crosstalk between RAF/MKK3/p38 signaling pathways during cell migration. Post-translational modifications can modify proteins and regulate their functions. Protein ubiquitylation is a post-translational modification that covalently attaches ubiquitin to target proteins, altering protein function in an extraordinary variety of ways. This process occurs in three sequential steps: ubiquitin activation by a ubiquitin-activating enzyme (E1); transfer of activated ubiquitin from E1 to ubiquitin-conjugating enzyme (E2); and conjugation of ubiquitin to a lysine residue of a substrate protein by ubiquitin ligase enzyme (E3). This catalytic process can be repeated over several cycles, resulting in substrates modified on multiple lysine residues with different poly-ubiquitin chains. Since E3 ligases control substrate specificity and the ubiquitylation topology, they are emerging as key regulators of cellular processes 1-3. Cell migration plays a fundamental role in multiple physiological and pathological processes, including wound healing, embryogenesis, tissue morphogenesis, cancer metastasis, and inflammation. Numerous studies have demonstrated that mitogen-activated protein kinase (MAPK) pathways, including the Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated protein kinase (ERK) signaling pathways, regulate cell migration via different mechanisms. Thus, the JNK signaling pathway modulates cell migration by phosphorylating proteins such as paxillin, DCX, Jun, and microtubule-associated proteins. Meanwhile, the p38 signaling pathway regulates migration by phosphorylating MAPK-activated protein kinase 2 (MAPKAP-K2 or MK2) and the ERK signaling pathway controls cell movement by phosphorylating myosin light chain kinase, calpain, or focal-adhesion kinase 4,5. Several ubiquitin E3 ligases also regulate cell migration by ubiquitylating the key proteins that control stress fiber form...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling

Pedrazza

Schneider

Bartrons

et al. 2020

Sci Rep

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“…In addition to the signaling cluster, ubiquitination also emerged as a distinct functional cluster with isoform-specific interactors ( Figure 5C). SEPT9_i1 associated with HERC1, an E3 ubiqutin ligase that degrades the proto-oncogene serine/threonine-protein kinase c-RAF (110).…”

Section: Functional Clustering Of the Sept9 Proteome Points To Isoformentioning

confidence: 99%

Proteomic profiling of the oncogenic septin 9 reveals isoform-specific interactions in breast cancer cells

Devlin

Perkins

Bowen

et al. 2019

Preprint

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Septins are a family of multimeric GTP-binding proteins, which are abnormally expressed in cancer. Septin 9 (SEPT9) is an essential and ubiquitously expressed septin with multiple isoforms, which have differential expression patterns and effects in breast cancer cells. It is unknown, however, if SEPT9 isoforms associate with different molecular networks and functions. Here, we performed a proteomic screen in MCF-7 breast cancer cells to identify the interactome of GFP-SEPT9 isoforms 1, 4 and 5, which vary significantly in their N-terminal extensions. While all three isoforms associated with SEPT2 and SEPT7, the truncated SEPT9_i4 and SEPT9_i5 interacted with septins of the SEPT6 group more promiscuously than SEPT9_i1, which bound predominately SEPT8. Spatial mapping and functional clustering of non-septin partners showed isoform-specific differences in interactions with proteins of distinct subcellular organelles (e.g., nuclei, centrosomes, cilia) and functions such as cell signaling and ubiquitination. Notably, the interactome of the full length SEPT9_i1 was more enriched in cytoskeletal regulators, while the truncated SEPT9_i4 and SEPT9_i5 exhibited preferential and isoform-specific interactions with nuclear, signaling and ubiquitinating proteins. These data provide evidence for isoform-specific interactions, which arise from truncations in the N-terminal extensions of SEPT9, and point to novel roles in the pathogenesis of breast cancer. L.D. performed experiments, analyzed data, made figures and co-wrote manuscript with E.T.S.; G.P. contributed technically and intellectually to ESI/LC-MS/MS experimentation and softwarebased peptide identification; J.R.B. performed microscopy imaging; C.M. created MCF-7 cell lines and contributed to the manuscript; E.T.S. conceived and directed the project (experiments and analyses), drafted manuscript and edited figures.

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E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development

Ioris

Ferris

D’Angiolella

2022

Inducing Targeted Protein Degradation

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The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

Cited by 34 publications

References 50 publications

The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling

The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling

Proteomic profiling of the oncogenic septin 9 reveals isoform-specific interactions in breast cancer cells

E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development

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