ArticleThe Journal of biological chemistry2015
Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Integrative Transcriptomic and Phosphoproteomic Analysis Reveals Key Components of the SnRK1 Signaling Network in Rice.Plant direct · 2025Article
- 5-Hydroxymethylcytosine profilings in circulating cell-free DNA as diagnostic biomarkers for DLBCL.Frontiers in cell and developmental biology · 2024Article
- Who's in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond.The Journal of cell biology · 2021Review
- Phosphoproteomic Analysis as an Approach for Understanding Molecular Mechanisms of cAMP-Dependent Actions.Molecular pharmacology · 2021Review
- An Arf/Rab cascade controls the growth and invasiveness of glioblastoma.The Journal of cell biology · 2021Article
- A novel DENND1B-localized structure found at the basal side of adherent cells.Histochemistry and cell biology · 2021Article
- Rab35-GEFs, DENND1A and folliculin differentially regulate podocalyxin trafficking in two- and three-dimensional epithelial cell cultures.The Journal of biological chemistry · 2020Article
- The lncRNAOncoTargets and therapy · 2020Article
- Colocalization of Polycystic Ovary Syndrome Candidate Gene Products in Theca Cells Suggests Novel Signaling Pathways.Journal of the Endocrine Society · 2019Article
- Molecular control of Rab activity by GEFs, GAPs and GDI.Small GTPases · 2018Review
- Intersectin-s interaction with DENND2B facilitates recycling of epidermal growth factor receptor.EMBO reports · 2017Article
- Rab-mediated vesicle trafficking in cancer.Journal of biomedical science · 2016Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Connecdenn 1/2 are DENN (differentially expressed in normal and neoplastic cells) domain-bearing proteins that function as GEFs (guanine nucleotide exchange factors) for the small GTPase Rab35. Disruption of connecdenn/Rab35 function leads to defects in the recycling of multiple cargo proteins from endosomes with altered cell function, yet the regulation of connecdenn GEF activity is unexplored. We now demonstrate that connecdenn 1/2 are autoinhibited such that the purified, full-length proteins have significantly less Rab35 binding and GEF activity than the isolated DENN domain. Both proteins are phosphorylated with prominent phosphorylation sites between residues 500 and 600 of connecdenn 1. A large scale proteomics screen revealed that connecdenn 1 is phosphorylated at residues Ser-536 and Ser-538 in an Akt-dependent manner in response to insulin stimulation of adipocytes. Interestingly, we find that an Akt inhibitor reduces connecdenn 1 interaction with Rab35 after insulin treatment of adipocytes. Remarkably, a peptide flanking Ser-536/Ser-538 binds the DENN domain of connecdenn 1, whereas a phosphomimetic peptide does not. Moreover, connecdenn 1 interacts with 14-3-3 proteins, and this interaction is also disrupted by Akt inhibition and by mutation of Ser-536/Ser-538. We propose that Akt phosphorylation of connecdenn 1 downstream of insulin activation regulates connecdenn 1 function through an intramolecular interaction.
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