ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion

Long, Weiwen; Foulds, Charles E.; Qin, Jun; Liu, J.; Chen, Ding; Lonard, David M.; Solis, Luisa M.; Wistuba, Ignacio I.; Tsai, Sophia Y.; Tsai, Ming Jer; O’Malley, Bert W.

doi:10.1172/jci61492

Cited by 122 publications

(216 citation statements)

References 39 publications

Supporting

Mentioning

195

Contrasting

Order By: Relevance

“…Therefore, it is tempting to speculate that a MyoD-USP20-ERK3 signaling pathway may play a role in skeletal muscle differentiation and physiology. Recent studies have shown that ERK3 stimulates the migration of lung and breast cancer cell lines (13,15). In agreement with these findings, we found that ERK3 overexpression increases the migration of HeLa cells.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity

Mathien

Déléris

Soulez

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogenactivated protein kinase (MAPK) whose regulatory mechanisms and biological functions remain superficially understood. Contrary to most protein kinases, ERK3 is a highly unstable protein that is subject to dynamic regulation by the ubiquitin-proteasome system. However, the effectors that control ERK3 ubiquitination and degradation are unknown. In this study, we carried out an unbiased functional loss-of-function screen of the human deubiquitinating enzyme (DUB) family and identified ubiquitin-specific protease 20 (USP20) as a novel ERK3 regulator. USP20 interacts with and deubiquitinates ERK3 both in vitro and in intact cells. The overexpression of USP20 results in the stabilization and accumulation of the ERK3 protein, whereas USP20 depletion reduces the levels of ERK3. We found that the expression levels of ERK3 correlate with those of USP20 in various cellular contexts. Importantly, we show that USP20 regulates actin cytoskeleton organization and cell migration in a manner dependent on ERK3 expression. Our results identify USP20 as a bona fide regulator of ERK3 stability and physiological functions.KEYWORDS deubiquitinating enzymes, ERK3, MAPKs E xtracellular signal-regulated kinase 3 (ERK3) along with its paralogous kinase ERK4 define a distinct subfamily of atypical mitogen-activated protein kinases (MAPKs) (1). ERK3 is expressed ubiquitously in adult mammalian tissues, with the highest levels being found in the central nervous system, skeletal muscle, lung, thymus, and testis (2-4). ERK4 shows a more restricted expression profile and is predominantly detected in brain tissue (4). Much remains to be learned about the substrates and physiological functions of these signaling enzymes. Unlike classical MAPKs, such as ERK1/ERK2, cJun NH 2 -terminal kinases, and p38s, that phosphorylate a large spectrum of substrates, ERK3 and ERK4 appear to have a restricted substrate specificity. Their best-characterized and validated substrate is the protein kinase MAPK-activated protein kinase 5 (MK5) (5-8). Genetic invalidation studies in mice have revealed important functions of ERK3 in fetal growth, pulmonary maturation, thymocyte development, and neuromuscular control (9-12). Biochemical and cellular studies also suggest that ERK3 plays key roles in transcriptional control, cell adhesion, cell migration, and the DNA damage response (13-16). The physiological functions of ERK4 are unknown.The activity of ERK3 and ERK4 is regulated in part by the phosphorylation of the Ser-Glu-Gly motif in the activation loop, which stimulates their intrinsic kinase activity and affinity for the substrate MK5 (17, 18). We and others have identified group I p21-activated kinases as ERK3/ERK4 activation loop kinases (19,20). Of note, the activating phosphorylation of ERK3/ERK4 is not modulated by classical MAPK stimuli or by any other extracellular stimuli tested, suggesting that other regulatory mechanisms control their biological activity (17). Citation Mathien S,...

show abstract

Section: Discussionsupporting

confidence: 92%

“…USP20 regulates cell adhesion and migration through ERK3. ERK3 has been proposed to regulate actin cytoskeleton dynamics and to promote cellular migration in various cell types (13)(14)(15). We therefore investigated the possible effect of USP20 on these cellular responses and the contribution of ERK3.…”

Section: Resultsmentioning

confidence: 99%

Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity

Mathien

Déléris

Soulez

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Consistently, mice with SRC-3 deletion had suppressed oncogene-and carcinogen-induced breast cancer initiation, progression, and metastasis (Kuang et al, 2004;Yi et al, 2013). Moreover, overexpression of SRC-3 has been frequently observed in a variety of other cancer types including lung, ovarian, liver, colorectal, pancreatic, and prostate cancers (Long et al, 2012;Palmieri et al, 2013;Geng et al, 2013). However, the biological function of SRC-3 in bladder cancer remains unexplored until now.…”

Section: Introductionmentioning

confidence: 92%

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

Wang¹,

Liu²,

Qu³

2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

The three homologous members of the p160 SRC family (SRC-1, SRC-2 and SRC-3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRC-3 gene is subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRC-3 promotes breast and prostate cancer cell proliferation and survival, have been identified. However, the function of SRC-3 in bladder cancer remains poorly understood. In the present study, our results indicate that overexpression of SRC-3 promotes bladder cancer cell proliferation whereas knockdown of SRC-3 results in inhibition. At the molecular level, we further established that CXCR4 is a transcriptional target of SRC-3. Therefore, our study first identified that SRC-3 plays a critical role in the bladder cancer, which may be a target beneficial for its prevention and treatment.

show abstract

“…Multiple kinases tend to modulate SRC-3 activity through various PTM codes, demonstrating the global role of SRC-3 in integrating upstream signaling events to promote aggressive progression in breast cancer. In addition to ER and PR, SRC-3 functionally activates other breast oncogenic transcription factors such as NFκB, PEA3, and IKK, and facilitates transcriptional upregulation of cancer-specific genes (21, 22, 27). Common downstream targets affected by SRC-3 activation include the insulin-like growth factor-1 (IGF1) pathway, cyclin D1, and MMPs (15).…”

Section: The Role Of Nuclear Receptor Coactivators In Human Disease Amentioning

confidence: 99%

Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease

2014

Self Cite

View full text Add to dashboard Cite

Transcriptional coregulators (coactivators and corepressors) have emerged as the principal modulators of the functions of nuclear receptors and other transcription factors. During the decade since the discovery of steroid receptor coactivator-1 (SRC-1), the first authentic coregulator, more than 400 coregulators have been identified and characterized, and deciphering their function has contributed significantly to our understanding of their role in human physiology. Deregulated expression of coregulators has been implicated in diverse disease states and related pathologies. The advancement of molecular technologies has enabled us to better characterize the molecular associations of the SRC family of coactivators with other protein complexes in the context of gene regulation. These continuing discoveries not only expand our knowledge of the roles of coactivators in various human diseases but allow us to discover novel coactivator-targeting strategies for therapeutic intervention in these diseases.

show abstract

ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion

Cited by 122 publications

References 39 publications

Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity

Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease

Contact Info

Product

Resources

About