scholarly journals A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking

2009 ◽  
Vol 186 (3) ◽  
pp. 343-353 ◽  
Author(s):  
Zhuojin Xu ◽  
Qiang Gong ◽  
Bin Xia ◽  
Benjamin Groves ◽  
Marc Zimmermann ◽  
...  
Keyword(s):  
Histone H3 ◽  
Adenosine Diphosphate ◽  
Endosomal Trafficking ◽  
Nucleotide Exchange ◽  
Recycling Endosomes ◽  
Guanine Nucleotide Exchange ◽  
Histone Lysine Methyltransferase ◽  
Nucleotide Exchange Factor ◽  
Cargo Proteins ◽  
Lysine Methyltransferase

Histone lysine methyltransferase complexes are essential for chromatin organization and gene regulation. Whether any of this machinery functions in membrane traffic is unknown. In this study, we report that mammal Dpy-30 (mDpy-30), a subunit of several histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) complexes, resides in the nucleus and at the trans-Golgi network (TGN). The TGN targeting of mDpy-30 is mediated by BIG1, a TGN-localized guanine nucleotide exchange factor for adenosine diphosphate ribosylation factor GTPases. Altering mDpy-30 levels changes the distribution of cation-independent mannose 6-phosphate receptor (CIMPR) without affecting that of TGN46 or transferrin receptor. Our experiments also indicate that mDpy-30 functions in the endosome to TGN transport of CIMPR and that its knockdown results in the enrichment of internalized CIMPR and recycling endosomes near cell protrusions. Much like mDpy-30 depletion, the knockdown of Ash2L or RbBP5, two other H3K4MT subunits, leads to a similar redistribution of CIMPR. Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins.

scholarly journals ARF-GEF cytohesin-2/ARNO regulates R-Ras and α5-integrin recycling through an EHD1-positive compartment

2015 ◽  
Vol 26 (23) ◽  
pp. 4265-4279 ◽  
Author(s):  
Joseph C. Salem ◽  
Marta M. Reviriego-Mendoza ◽  
Lorraine C. Santy
Keyword(s):  
Adhesion Formation ◽  
Small Gtpases ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Recycling Endosomes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
And Migration ◽  
Regulated Trafficking ◽  
Migration Response

When expressed in epithelial cells, cytohesin-2/ARNO, a guanine nucleotide exchange factor (GEF) for ARF small GTPases, causes a robust migration response. Recent evidence suggests that cytohesin-2/ARNO acts downstream of small the GTPase R-Ras to promote spreading and migration. We hypothesized that cytohesin-2/ARNO could transmit R-Ras signals by regulating the recycling of R-Ras through ARF activation. We found that Eps15-homology domain 1 (EHD1), a protein that associates with the endocytic recycling compartment (ERC), colocalizes with active R-Ras in transiently expressed HeLa cells. In addition, we show that EHD1-positive recycling endosomes are a novel compartment for cytohesin-2/ARNO. Knockdown or expression of GEF-inactive (E156K) cytohesin-2/ARNO causes R-Ras to accumulate on recycling endosomes containing EHD1 and inhibits cell spreading. E156K-ARNO also causes a reduction in focal adhesion size and number. Finally, we demonstrate that R-Ras/ARNO signaling is required for recycling of α5-integrin and R-Ras to the plasma membrane. These data establish a role for cytohesin-2/ARNO as a regulator of R-Ras and integrin recycling and suggest that ARF-regulated trafficking of R-Ras is required for R-Ras–dependent effects on spreading and adhesion formation.

scholarly journals An Arf/Rab cascade controls the growth and invasiveness of glioblastoma

2021 ◽  
Vol 220 (2) ◽  
Author(s):  
Gopinath Kulasekaran ◽  
Mathilde Chaineau ◽  
Valerio Emilio Crescenzo Piscopo ◽  
Federica Verginelli ◽  
Maryam Fotouhi ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Growth Factor Receptor ◽  
Endosomal Trafficking ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Tumor Initiating Cells ◽  
Human Brain Tumor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Brain Tumor Initiating Cells

Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brains. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn, and allosterically enhances its GEF activity toward Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness, and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals up-regulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor, with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.

scholarly journals Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling

2012 ◽  
Vol 23 (14) ◽  
pp. 2723-2740 ◽  
Author(s):  
Steve Jean ◽  
Sarah Cox ◽  
Eric J. Schmidt ◽  
Fred L. Robinson ◽  
Amy Kiger
Keyword(s):  
Endosomal Trafficking ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Phosphatidylinositol 3 Kinase ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Membrane Compartment ◽  
Endosomal Pathway ◽  
Gtpase Activation ◽  
Phosphatidylinositol 3

Cells rely on the coordinated regulation of lipid phosphoinositides and Rab GTPases to define membrane compartment fates along distinct trafficking routes. The family of disease-related myotubularin (MTM) phosphoinositide phosphatases includes catalytically inactive members, or pseudophosphatases, with poorly understood functions. We found that Drosophila MTM pseudophosphatase Sbf coordinates both phosphatidylinositol 3-phosphate (PI(3)P) turnover and Rab21 GTPase activation in an endosomal pathway that controls macrophage remodeling. Sbf dynamically interacts with class II phosphatidylinositol 3-kinase and stably recruits Mtm to promote turnover of a PI(3)P subpool essential for endosomal trafficking. Sbf also functions as a guanine nucleotide exchange factor that promotes Rab21 GTPase activation associated with PI(3)P endosomes. Of importance, Sbf, Mtm, and Rab21 function together, along with Rab11-mediated endosomal trafficking, to control macrophage protrusion formation. This identifies Sbf as a critical coordinator of PI(3)P and Rab21 regulation, which specifies an endosomal pathway and cortical control.

scholarly journals A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Katja Gotthardt ◽  
Mandy Lokaj ◽  
Carolin Koerner ◽  
Nathalie Falk ◽  
Andreas Gießl ◽  
...  
Keyword(s):  
G Protein ◽  
Joubert Syndrome ◽  
Nucleotide Exchange ◽  
Protein Activation ◽  
Guanine Nucleotide Exchange ◽  
Mammalian Cell Lines ◽  
Nucleotide Exchange Factor ◽  
Cargo Proteins ◽  
Switch Regions ◽  
Activation Cascade

Small G-proteins of the ADP-ribosylation-factor-like (Arl) subfamily have been shown to be crucial to ciliogenesis and cilia maintenance. Active Arl3 is involved in targeting and releasing lipidated cargo proteins from their carriers PDE6δ and UNC119a/b to the cilium. However, the guanine nucleotide exchange factor (GEF) which activates Arl3 is unknown. Here we show that the ciliary G-protein Arl13B mutated in Joubert syndrome is the GEF for Arl3, and its function is conserved in evolution. The GEF activity of Arl13B is mediated by the G-domain plus an additional C-terminal helix. The switch regions of Arl13B are involved in the interaction with Arl3. Overexpression of Arl13B in mammalian cell lines leads to an increased Arl3·GTP level, whereas Arl13B Joubert-Syndrome patient mutations impair GEF activity and thus Arl3 activation. We anticipate that through Arl13B’s exclusive ciliary localization, Arl3 activation is spatially restricted and thereby an Arl3·GTP compartment generated where ciliary cargo is specifically released.

scholarly journals An Arf/Rab cascade controls the growth and invasiveness of glioblastoma

2020 ◽  
Author(s):  
Gopinath Kulasekaran ◽  
Mathilde Chaineau ◽  
Valerio E. Piscopo ◽  
Federica Verginelli ◽  
Maryam Fotouhi ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Growth Factor Receptor ◽  
Endosomal Trafficking ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Tumor Initiating Cells ◽  
Human Brain Tumor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Brain Tumor Initiating Cells

AbstractGlioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brain. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn and allosterically enhances its GEF activity towards Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals upregulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.

scholarly journals Rabin8 regulates neurite outgrowth in both GEF activity–dependent and –independent manners

2016 ◽  
Vol 27 (13) ◽  
pp. 2107-2118 ◽  
Author(s):  
Yuta Homma ◽  
Mitsunori Fukuda
Keyword(s):  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Membrane Trafficking ◽  
Small Gtpases ◽  
Nucleotide Exchange ◽  
Recycling Endosomes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Activity Dependent

Many aspects of membrane-trafficking events are regulated by Rab-family small GTPases. Neurite outgrowth requires massive addition of proteins and lipids to the tips of growing neurites by membrane trafficking, and although several Rabs, including Rab8, Rab10, and Rab11, have been implicated in this process, their regulatory mechanisms during neurite outgrowth are poorly understood. Here, we show that Rabin8, a Rab8-guanine nucleotide exchange factor (GEF), regulates nerve growth factor (NGF)–induced neurite outgrowth of PC12 cells. Knockdown of Rabin8 results in inhibition of neurite outgrowth, whereas overexpression promotes it. We also find that Rab10 is a novel substrate of Rabin8 and that both Rab8 and Rab10 function during neurite outgrowth downstream of Rabin8. Surprisingly, however, a GEF activity–deficient isoform of Rabin8 also promotes neurite outgrowth, indicating the existence of a GEF activity–independent role of Rabin8. The Arf6/Rab8-positive recycling endosomes (Arf6/Rab8-REs) and Rab10/Rab11-positive REs (Rab10/Rab11-REs) in NGF-stimulated PC12 cells are differently distributed. Rabin8 localizes on both RE populations and appears to activate Rab8 and Rab10 there. These localizations and functions of Rabin8 are Rab11 dependent. Thus Rabin8 regulates neurite outgrowth both by coordinating with Rab8, Rab10, and Rab11 and by a GEF activity–independent mechanism.

scholarly journals Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e413-e416
Author(s):  
Julia Körholz ◽  
Nadja Lucas ◽  
Franziska Boiti ◽  
Karina Althaus ◽  
Oliver Tiebel ◽  
...  
Keyword(s):  
Platelet Function ◽  
Adenosine Diphosphate ◽  
Severe Bleeding ◽  
Bleeding Diathesis ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Whole Exome ◽  
Platelet Function Disorders ◽  
Diagnostic Work

AbstractNext-generation sequencing is increasingly applied during the diagnostic work-up of patients with bleeding diathesis and has facilitated the diagnosis of rare bleeding disorders such as inherited platelet function disorders. Mutations in RAS guanyl releasing protein 2 (RasGRP2), also known as calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), underlie a recently described platelet signal transduction abnormality. Here we present the case of a consanguineous family originating from Afghanistan with two siblings affected by recurrent severe mucocutaneous bleedings. Platelet function testing demonstrated a marked reduction of aggregation induced by collagen and adenosine diphosphate. Whole exome sequencing revealed a novel homozygous nonsense RASGRP2 mutation segregating with the bleeding disorder in the family.

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