The Connecdenn DENN Domain: A GEF for Rab35 Mediating Cargo-Specific Exit from Early Endosomes

Allaire, Patrick D.; Marat, Andrea L.; Dall’Armi, Claudia; Paolo, Gilbert Di; McPherson, Peter S.; Ritter, Brigitte

doi:10.1016/j.molcel.2009.12.037

Cited by 184 publications

(276 citation statements)

References 48 publications

(74 reference statements)

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“…DENND1A.V2 is a truncated connecdenn 1, which has a clathrinbinding domain and is thought to facilitate endocytosis. Among the loci associated with PCOS in Han Chinese, several reside in or near genes that potentially define a network, including FSHR, LHCGR, and INSR, which encode receptors that reside on the plasma membrane and which are internalized by clathrin-coated pits, where the DENND1A protein is located (24,25,33). The DENN domains of DENND1A function as Rab-specific guanine nucleotide-exchange factors.…”

Section: Discussionmentioning

confidence: 99%

“…Ras related protein 5B (RAB5B), another PCOS GWAS candidate, is a Rab-GTPase, also thought to be involved in endocytosis and receptor recycling and could, therefore, be a molecule interacting with the DENN domain (40,41). RAB5B signaling has also been reported to involve PI3K, PKB, and MAPK/ERK components (33,(40)(41)(42). Therefore, the truncated form of DENND1A.V2 could potentially affect insulin or luteinizing hormone (LH)-receptor turnover and sensitivity in theca and granulosa cells, further affecting ovarian function and steroid biosynthesis in PCOS women.…”

Section: Discussionmentioning

confidence: 99%

“…The source of the urine exosomal DENND1A mRNA is not known. The kidney expresses the DENND1A gene, and it is a likely source (26,33). If this is indeed the case, the finding of increased DENND1A.V2 mRNA in urine speaks to a generalized alteration in expression of this variant in PCOS.…”

Section: Discussionmentioning

confidence: 99%

“…The DENN domains function as Rab-specific guanine nucleotide-exchange factors (31,32). The DENND1A gene consists of 22 exons extending over 500,000 bases, and encodes protein connecdenn 1, which has a clathrinbinding domain and is thought to facilitate endocytosis and receptor-mediated turnover (31,33,34). Connecdenn 1 is a guanine nucleotide-exchange factor that interacts with members of the Rab family of small GTPases, which are involved in membrane trafficking (31).…”

Section: Significancementioning

confidence: 99%

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Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

191

157

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Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. P olycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women world-wide (1). PCOS is associated with hyperandrogenemia/ hyperandrogenism, anovulation, infertility, and a characteristic ovarian morphology consisting of multiple small subcortical follicular "cysts" embedded in bilaterally enlarged ovaries (2-5). The presence of elevated circulating concentrations of testosterone results primarily from increased production of androgens by the ovaries, and is a classic endocrine phenotype of women with PCOS. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism and anovulation, not explained by other causes, is a hallmark of the disorder, and is included as a key element in all "consensus" diagnosis schemes (6-10).There is consensus that the ovarian theca cells are the primary source of excess androgen biosynthesis in women with PCOS (11-13). Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

191

157

View full text Add to dashboard Cite

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“…Rab proteins are further regulated by a diverse group of structurally unrelated GDP-GTP exchange factors and a family of GTP-hydrolysis-activating proteins 40,41 . For example, various DENN domains interact directly with members of the Rab family of small GTPases, and DENN (differentially expressed in normal and neoplastic cells) domains function enzymatically as Rab-specific guanine nucleotide exchange factors 42,43 . There are 18 genes encoding DENN domaincontaining proteins in humans 44 .…”

Section: Discussionmentioning

confidence: 99%

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

et al. 2013

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Cytoplasmic dynein drives the movement of a wide range of cargoes towards the minus ends of microtubules. We previously demonstrated that LIS1 forms an idling complex with dynein, which is transported to the plus ends of microtubules by kinesin motors. Here we report that the small GTPase Rab6a is essential for activation of idling dynein. Immunoprecipitation and microtubule pull-down assays reveal that the GTP bound mutant, Rab6a(Q72L), dissociates LIS1 from a LIS1-dynein complex, activating dynein movement in in vitro microtubule gliding assays. We monitor transient interaction between Rab6a(Q72L) and dynein in vivo using dual-colour fluorescence cross-correlation spectroscopy in dorsal root ganglion (DRG) neurons. Finally, we demonstrate that Rab6a(Q72L) mediates LIS1 release from a LIS1-dynein complex followed by dynein activation through an in vitro single-molecule assay using triplecolour quantum dots. Our findings reveal a surprising function for GTP bound Rab6a as an activator of idling dynein.

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Phosphoinositides and cytokinesis: The “PIP” of the iceberg

Échard

2012

Cytoskeleton

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Phosphoinositides[Phosphatidylinositol (PtdIns), phosphatidylinositol 3-monophosphate (PtdIns3P), phosphatidylinositol 4-monophosphate (PtdIns4P), phosphatidylinositol 5-monophosphate (PtdIns5P), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 ), phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2 ), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 )] are lowly abundant acidic lipids found at the cytosolic leaflet of the plasma membrane and intracellular membranes. Initially discovered as precursors of second messengers in signal transduction, phosphoinositides are now known to directly or indirectly control key cellular functions, such as cell polarity, cell migration, cell survival, cytoskeletal dynamics, and vesicular traffic. Phosphoinositides actually play a central role at the interface between membranes and cytoskeletons and contribute to the identity of the cellular compartments by recruiting specific proteins. Increasing evidence indicates that several phosphoinositides, particularly PtdIns(4,5)P 2 , are essential for cytokinesis, notably after furrow ingression. The present knowledge about the specific phosphoinositides and phosphoinositide modifying-enzymes involved in cytokinesis will be first presented. The review of the current data will then show that furrow stability and cytokinesis abscission require that both phosphoinositide production and hydrolysis are regulated in space and time. Finally, I will further discuss recent mechanistic insights on how phosphoinositides regulate membrane trafficking and cytoskeletal remodeling for successful furrow ingression and intercellular bridge abscission. This will highlight unanticipated connections between cytokinesis and enzymes implicated in human diseases, such as the Lowe syndrome. V C 2012 Wiley Periodicals, Inc

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The Connecdenn DENN Domain: A GEF for Rab35 Mediating Cargo-Specific Exit from Early Endosomes

Cited by 184 publications

References 48 publications

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

Phosphoinositides and cytokinesis: The “PIP” of the iceberg

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