α-Arrestins – new players in Notch and GPCR signaling pathways in mammals

Puca, Loredana; Brou, Christel

doi:10.1242/jcs.142539

Cited by 61 publications

(79 citation statements)

References 82 publications

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“…ARRDC3 possesses arrestin-like N-and C-domains and Cterminal PPxY motifs that bind to WW domains of HECT-domain containing E3 ubiquitin ligases (48,49). Despite the presence of arrestin-like domains, the α-arrestin ARRDC3 appears to lack a polar core, which is essential for β-arrestin binding to activated and phosphorylated GPCRs (50). In addition, β-arrestins lack C-terminal PPxY motifs, indicating that a-arrestin and b-arrestin proteins likely have divergent functions.…”

Section: Discussionmentioning

confidence: 99%

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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Aberrant G protein-coupled receptor (GPCR) expression and activation has been linked to tumor initiation, progression, invasion and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. Therefore, to advance the potential status of GPCRs as therapeutic targets, it is important to understand how GPCRs function together with other cancer drivers during tumor progression. We now report that the a-arrestin domain-containing protein-3 (ARRDC3) acts as a tumor suppressor in part by controlling signaling and trafficking of the GPCR, protease-activated receptor-1 (PAR1). In a series of highly invasive basal-like breast carcinomas, we found that expression of ARRDC3 is suppressed while PAR1 is aberrantly overexpressed because of defective lysosomal sorting that results in persistent signaling. Using a lentiviral doxycycline-inducible system, we demonstrate that re-expression of ARRDC3 in invasive breast carcinoma is sufficient to restore normal PAR1 trafficking through the ALGinteracting protein X (ALIX)-dependent lysosomal degradative pathway. We also show that ARRDC3 re-expression attenuates PAR1-stimulated persistent signaling of c-Jun NH2-terminal kinase (JNK) in invasive breast cancer. Remarkably, restoration of ARRDC3 expression significantly reduced activated PAR1-induced breast carcinoma invasion, which was also dependent on JNK signaling. These findings are the first to identify a critical link between the tumor suppressor ARRDC3 and regulation of GPCR trafficking and signaling in breast cancer.G protein-coupled receptors (GPCRs) are a large family of cell surface signaling receptors that play a critical role in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites (1-3). GPCR function can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, mutations in downstream G protein signaling effectors, and increased production and secretion of GPCR activating ligands by both tumor cells and surrounding stromal cells (4-7). As cell surface receptors with highly druggable sites, GPCRs are the largest class of drug targets, with over 30% of current FDAhttp://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 99%

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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“…Recent studies classified the arrestin family into visual-arrestins, β-arrestins (e.g., β-arrestin2), and α-arrestins (ARRDCs in mammals) [44]. Although α-arrestins are mainly membrane-associated proteins, recent studies indicated that they change their subcellular localization in response to different stimuli [44].…”

Section: Discussionmentioning

confidence: 99%

Gene expression and immunohistochemical analyses of mKast suggest its late pupal and adult-specific functions in the honeybee brain

et al. 2017

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In insect brains, the mushroom bodies (MBs, a higher center) comprise intrinsic neurons, termed Kenyon cells (KCs). We previously showed that the honeybee (Apis mellifera L.) MBs comprise four types of KCs, in addition to the previously known three types of KCs: class I large-type KCs (lKCs), class I small-type KCs (sKCs) and class II KCs, novel class I ‘middle-type’ KCs (mKCs), which are characterized by the preferential expression of a gene, termed mKast. Although mKast was originally discovered during the search for genes whose expression is enriched in the optic lobes (OLs) in the worker brain, subsequent analysis revealed that the gene is expressed in an mKC-preferential manner in the MBs. To gain more insights into the function of mKast in the honeybee brain, we here performed expression analysis of mKast and immunohistochemistry of the mKast protein. Prominent mKast expression was first detected in the brain after the P7 pupal stage. In addition, mKast was expressed almost selectively in the brain, suggesting its late pupal and adult specific functions in the brain. Immunohistochemistry revealed that mKast-like immunoreactivity is detected in several regions in the worker brain: inside and around the MB calyces, at the outer edges of the OL lobula, at the outer surface of and posterior to the antennal lobes (ALs), along the dorsal midline of the anterior brain and at the outer surface of the subesophageal ganglions (SOG). mKast-like immunoreactivities in the MBs, OLs, ALs and SOG were due to the corresponding neurons, while mKast-like immunoreactivities beneath/between the MB calyces were assumed to most likely correspond to the lateral/medial neurosecretory cells.

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“…Second, SIMPLE interacts with Nedd4 E3 ubiquitin ligases via the PPXY motifs (34,37). PPXY motifs are also found in all of the ␣-arrestin proteins except the Arrdc5 member (79,80). Third, SIMPLE encodes a PTAP motif for its interaction with ESCRT-1 protein Tsg101 (34,37).…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

Zhu

Zhao

et al. 2015

Molecular and Cellular Biology

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Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along with endosomal sorting complex required for transport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs puncta in late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor ␤, prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-B and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.

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α-Arrestins – new players in Notch and GPCR signaling pathways in mammals

Cited by 61 publications

References 82 publications

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Gene expression and immunohistochemical analyses of mKast suggest its late pupal and adult-specific functions in the honeybee brain

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

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