Structure-function analyses of the human SIX1–EYA2 complex reveal insights into metastasis and BOR syndrome

Patrick, Aaron; Cabrera, Joshua H.; Smith, Anna; Chen, Xiaojiang S.; Ford, Heide L.; Zhao, Rui

doi:10.1038/nsmb.2505

Cited by 103 publications

(169 citation statements)

References 69 publications

Supporting

Mentioning

159

Contrasting

Order By: Relevance

“…We also noted that the G426S, D429G, and R440Q variants displayed a slight increase of ubiquitination, even though they may have comparable levels of tyrosine phosphatase activity in vitro (23,27). Structural and site-directed mutator (SDM) analysis suggests that the S487P, G426S, D429G, and R440Q mutants have minimal impact on the overall structural integrity of the Eya1 protein (9). The aberrant modification patterns of diseased forms of Eya1, including S487P, L505R, and E362K, suggest that dysregulation of human EYA1 protein stability could contribute to BOR syndrome.…”

Section: Resultsmentioning

confidence: 99%

“…To examine the potential pathophysiological significance of Eya1 ubiquitin modification, we analyzed a number of missense mutations within the conserved C-terminal domain identified in patients with BOR syndrome (9,25,26). Among them, the S487P and L505R point mutants have a significantly lower level of tyrosine phosphatase catalytic activity (23,27).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

Sun

2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is selflimited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1 ؉/؊ ; Wnt9b ؉/؊ mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

Sun

2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Although SIX1 expression in most adult tissues is rare, upregulation of this transcription factor has been detected in over ten different cancers, including tumors that arise from skeletal muscle tissue, called rhabdomyosarcoma (RMS) (Christensen et al, 2008;Patrick et al, 2013;Yu et al, 2004). Interestingly, the expression of miR30a decreases with the progression of lymphoma, leukemia, lung, ovarian, breast and colon cancer (Cheng et al, 2012;González-Gugel et al, 2013;Guan et al, 2012;Lee et al, 2012;Liu et al, 2013;Ma et al, 2012;Võsa et al, 2013), all cancers in which SIX1 overexpression has been detected (Behbakht et al, 2007;Ford et al, 1998;Mimae et al, 2012;Ono et al, 2012;Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-30a regulates zebrafish myogenesis via targeting the transcription factor Six1

O’Brien

Hernandez-Lagunas

Artinger

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Precise spatiotemporal regulation of the SIX1 homeoprotein is required to coordinate vital tissue development, including myogenesis. Whereas SIX1 is downregulated in most tissues following embryogenesis, it is re-expressed in numerous cancers, including tumors derived from muscle progenitors. Despite crucial roles in development and disease, the upstream regulation of SIX1 expression has remained elusive. Here, we identify the first direct mechanism for Six1 regulation in embryogenesis, through microRNA30a (miR30a)-mediated repression. In zebrafish somites, we show that miR30a and six1a and six1b (hereafter six1a/b) are expressed in an inverse temporal pattern. Overexpression of miR30a leads to a reduction in six1a/b levels, and results in increased apoptosis and altered somite morphology, which phenocopies six1a/b knockdown. Conversely, miR30a inhibition leads to increased Six1 expression and abnormal somite morphology, revealing a role for endogenous miR30a as a muscle-specific miRNA (myomiR). Importantly, restoration of six1a in miR30a-overexpressing embryos restores proper myogenesis. These data demonstrate a new role for miR30a at a key node in the myogenic regulatory gene network through controlling Six1 expression.

show abstract

“…These results suggested that Eya2 was capable of conferring an aberrant self-renewal capacity on hematopoietic stem and/or progenitor cells without differentiation block in the myeloid lineage. To investigate the molecular mechanism of immortalization by Eya2, several Eya2 mutants were generated on the basis of previous findings (24,33) and subjected to myeloid immortalization assays (Fig. 3A to C).…”

mentioning

confidence: 99%

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Ono

Masuya

Ishii

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-

show abstract

Structure-function analyses of the human SIX1–EYA2 complex reveal insights into metastasis and BOR syndrome

Cited by 103 publications

References 69 publications

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

MicroRNA-30a regulates zebrafish myogenesis via targeting the transcription factor Six1

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Contact Info

Product

Resources

About