Neuron Specific Rab4 Effector GRASP-1 Coordinates Membrane Specialization and Maturation of Recycling Endosomes

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.

Download Full-text

Role of BMP receptor traffic in synaptic growth defects in an ALS model

Molecular Biology of the Cell ◽

10.1091/mbc.e16-07-0519 ◽

2016 ◽

Vol 27 (19) ◽

pp. 2898-2910 ◽

Cited By ~ 22

Author(s):

Mugdha Deshpande ◽

Zachary Feiger ◽

Amanda K. Shilton ◽

Christina C. Luo ◽

Ethan Silverman ◽

...

Keyword(s):

Neurological Impairment ◽

Bmp Signaling ◽

Loss Of Function ◽

Gain Of Function ◽

Synaptic Growth ◽

Recycling Endosome ◽

Recycling Endosomes ◽

Bmp Receptor ◽

Bmp Receptors ◽

Induced Defects

TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment.

Download Full-text

VAMP4 cycles from the cell surface to the trans-Golgi network via sorting and recycling endosomes

Journal of Cell Science ◽

10.1242/jcs.03387 ◽

2007 ◽

Vol 120 (6) ◽

pp. 1028-1041 ◽

Cited By ~ 42

Author(s):

T. H. T. Tran ◽

Q. Zeng ◽

W. Hong

Keyword(s):

Cell Surface ◽

Recycling Endosomes ◽

Trans Golgi Network ◽

Golgi Network

Download Full-text

Trafficking of interleukin 2 and transferrin in endosomal fractions of T lymphocytes

Journal of Cell Science ◽

10.1242/jcs.107.5.1289 ◽

1994 ◽

Vol 107 (5) ◽

pp. 1289-1295 ◽

Cited By ~ 1

Author(s):

V. Duprez ◽

M. Smoljanovic ◽

M. Lieb ◽

A. Dautry-Varsat

Keyword(s):

Horseradish Peroxidase ◽

Interleukin 2 ◽

Fluid Phase ◽

Endocytic Pathway ◽

Recycling Endosomes ◽

High Affinity ◽

Human T Cell ◽

Late Endosomes ◽

Discontinuous Sucrose Gradient ◽

Acidic Organelles

The T lymphocyte growth factor interleukin 2 binds to surface high-affinity receptors and is rapidly internalized and degraded in acidic organelles. The alpha and beta chains of high-affinity interleukin 2 receptors are internalized together with interleukin 2. To identify the intracellular pathway followed by interleukin 2, we have compared the subcellular distribution of interleukin 2, transferrin and a fluid-phase marker, horseradish peroxidase, in the human T cell line IARC 301.5. Transferrin was used as a marker of early and recycling endosomes, and horseradish peroxidase to probe for the whole endocytic pathway. Fractionation of intracellular organelles on a discontinuous sucrose gradient showed that internalized interleukin 2 is initially mostly found in compartments with similar densities to transferrin, e.g. early and recycling endosomes. The kinetics of entry and exit of interleukin 2 from such organelles was much slower than that of transferrin. Later on, interleukin 2 is predominantly found in dense lysosome-containing fractions. Very little, if any, interleukin 2 was found in fractions corresponding to late endosomes containing horseradish peroxidase. These results suggest that, after endocytosis, interleukin 2 enters early or recycling endosomes before it reaches dense lysosomes.

Download Full-text