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 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 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 PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2 mediated phosphorylation at Threonine72

2019 ◽  
Author(s):  
Sophie Vieweg ◽  
Katie Mulholland ◽  
Bastian Bräuning ◽  
Nitin Kachariya ◽  
Yu-Chiang Lai ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Therapeutic Potential ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Lrrk2 Kinase ◽  
Genetic Code Expansion

AbstractLoss of function mutations in the PINK1 kinase are causal for autosomal recessive Parkinson disease (PD) whilst gain of function mutations in the LRRK2 kinase cause autosomal dominant PD. PINK1 indirectly regulates the phosphorylation of a subset of Rab GTPases at a conserved Serine111 (Ser111) residue within the SF3 motif. Using genetic code expansion technologies we have produced stoichiometric Ser111-phosphorylated Rab8A revealing impaired interactions with its cognate guanine nucleotide exchange factor (GEF) and GTPase activating protein (GAP). In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2. Strikingly we demonstrate that Ser111 phosphorylation negatively regulates the ability of LRRK2 but not MST3 or TAK1 to phosphorylate Thr72 in vitro and demonstrate an interplay of PINK1- and LRRK2-mediated phosphorylation of Rab8A in cells. Finally, we present the crystal structure of Ser111-phosphorylated Rab8A and NMR structure of Ser111-phosphorylated Rab1B that does not demonstrate any major changes suggesting that the phosphorylated SF3 motif may disrupt effector-Switch II interactions. Overall, we demonstrate antagonistic regulation between PINK1-dependent Ser111 phosphorylation and LRRK2-mediated Thr72 phosphorylation of Rab8A suggesting that small molecule activators of PINK1 may have therapeutic potential in patients harbouring LRRK2 mutations.

scholarly journals The NCA-1 and NCA-2 ion channels function downstream of Gq and Rho to regulate locomotion in C. elegans

2016 ◽  
Author(s):  
Irini Topalidou ◽  
Pin-An Chen ◽  
Kirsten Cooper ◽  
Shigeki Watanabe ◽  
Erik M. Jorgensen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
C Elegans ◽  
Activating Mutations ◽  
Epistasis Analysis ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Forward Genetic Screens ◽  
Genetic Epistasis

AbstractThe heterotrimeric G protein Gq positively regulates neuronal activity and synaptic transmission. Previously, the Rho guanine nucleotide exchange factor Trio was identified as a direct effector of Gq that acts in parallel to the canonical Gq effector phospholipase C. Here we examine how Trio and Rho act to stimulate neuronal activity downstream of Gq in the nematode Caenorhabditis elegans. Through two forward genetic screens, we identify the cation channels NCA-1 and NCA-2, orthologs of mammalian NALCN, as downstream targets of the Gq/Rho pathway. By performing genetic epistasis analysis using dominant activating mutations and recessive loss-of-function mutations in the members of this pathway, we show that NCA-1 and NCA-2 act downstream of Gq in a linear pathway. Through cell-specific rescue experiments, we show that function of these channels in head acetylcholine neurons is sufficient for normal locomotion in C. elegans. Our results suggest that NCA-1 and NCA-2 are physiologically relevant targets of neuronal Gq-Rho signaling in C. elegans.

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.

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