Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein

Teng, Yong; Ren, Xiaoou; Li, Honglin; Shull, Austin Y.; Kim, Jaejik; Cowell, John K.

doi:10.1038/onc.2015.86

Cited by 84 publications

(117 citation statements)

References 45 publications

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“…The ATCC Cell Authentication Testing service confirmed the identity of Hs578T and PC3 cells using STR DNA fingerprinting analysis (08/15/15). Lentiviral transduction, cell proliferation assays, wound healing assays, Transwell invasion assays, western blotting, flow cytometry and Real-time RT-PCR analysis were carried out as described previously (9–11,15–17). …”

Section: Methodsmentioning

confidence: 99%

“…Although primarily considered a protein that regulates actin cytoskeleton dynamics, WASF3 has also been shown to have a regulatory function that affects expression of genes involved in metastasis such as KISS1, ZEB1 and miRNA-200s (10–12) and its activity and expression is regulated by proteins such as JAK2, HSP70, ABL and HIF1 (13–16), which have also been implicated in metastasis. WASF3 also interacts with the ATAD3A mitochondrial protein, which regulates its stability at the mitochondrial membrane (17). …”

Section: Introductionmentioning

confidence: 99%

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Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

et al. 2016

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Activation of the WASF3 protein by extracellular stimuli promotes actin cytoskeleton reorganization and facilitates cancer cell invasion, whereas WASF3 depletion suppresses invasion and metastasis. In quiescent cells, the interaction between WASF3 and a complex of proteins including CYFIP1 acts as a conformational restraint to prevent WASF3 activation. Therefore, we took advantage of this endogenous regulatory mechanism to investigate potential sites that disrupt WASF3 function. Here, we show that genetic knockdown of CYFIP1 in cancer cells led to the destabilization of the WASF3 complex, loss of WASF3 function, and suppressed invasion. Based on existing crystallographic data, we developed stapled peptides, referred to as WASF Helix Mimics (WAHM), that target an α-helical interface between WASF3 and CYFIP1. Treatment of highly invasive breast and prostate cancer cells with WAHM inhibitor peptides significantly reduced motility and invasion in vitro. Mechanistic investigations revealed that these inhibitors suppressed the interaction between Rac and the WASF3 complex, which has been shown to promote cell migration. Furthermore, peptide-mediated inhibition of WASF3 also resulted in the dysregulation of known downstream targets such as MMP-9 and KISS1. Finally, we demonstrate that this invasive phenotype is specific to WASF3 as depletion of WASF1 and WASF2, which can also bind to CYFIP1, did not affect invasion. Collectively, our findings suggest that targeting WASF3 function with WAHM peptides could represent a promising therapeutic strategy for preventing tumor invasion and metastasis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

et al. 2016

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“…WASF3 upregulation leads to downregulation of E-cadherin and members of the miR-200 family (25), both of which have been shown to suppress epithelial-to mesenchyme transition (EMT). WASF3 can also be upregulated by HIF1 as a result of hypoxia (26) and facilities communication between endoplasmic reticulum and mitochondria through its interaction with the ATAD3A mitochondrial protein and GRP78 (27). …”

Section: Introductionmentioning

confidence: 99%

The WASF3–NCKAP1–CYFIP1 Complex Is Essential for Breast Cancer Metastasis

et al. 2016

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Inactivation of the WASF3 gene suppresses invasion and metastasis of breast cancer cells. WASF3 function is regulated through a protein complex that includes the NCKAP1 and CYFIP1 proteins. Here we report that silencing NCKAP1 destabilizes the WASF3 complex, resulting in a suppression of the invasive capacity of breast, prostate and colon cancer cells. In an in vivo model of spontaneous metastasis in immunocompromized mice, loss of NCKAP1 also suppresses metastasis. Activation of the WASF protein complex occurs through interaction with RAC1, and inactivation of NCKAP1 prevents the association of RAC1 with the WASF3 complex. Thus, WASF3 depends on NCKAP1 to promote invasion and metastasis. Here we show that stapled peptides targeting the interface between NCKAP1 and CYFIP1 destabilize the WASF3 complex and suppress RAC1 binding, thereby suppressing invasion. Using a complex-disrupting compound identified in this study termed WANT3, our results offer a mechanistic proof of concept to target this interaction as a novel approach to inhibit breast cancer metastasis.

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“…ATAD3A interacts simultaneously with both mitochondrial membranes and therefore, it regulates mitochondrial dynamics at the interface between the IMM and OMM and is involved in several cell responses, such as cell growth, enhanced channeling of cholesterol for hormone-dependent steroidogenesis (178)(179)(180) and mitochondrial fission (178). It was also shown to play a role in mtDNA maintenance and replication (181), as well as cancer cell growth and metastasis (182). Loss of function of ATAD3A at contact sites between the OMM and IMM was shown to induce cell fission machinery (178).…”

Section: Atpase Family Aaa-domain Containing Protein 3a (Atad3a)mentioning

confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein

Cited by 84 publications

References 45 publications

Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

The WASF3–NCKAP1–CYFIP1 Complex Is Essential for Breast Cancer Metastasis

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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