Biology subjects

Jung, P.

Publications and source records attributed to Jung, P..

6 recordsLinked to original sources

bioRxiv2023

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2-phosphatase, PTEN. Despite huge investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. A poorly understood, YXXM and PIP3/PI(3,4)P2-binding PH domain-containing, adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT-phosphorylation and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K and SRC-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1-mRNA and activating-Y419-phosphorylation of hSRC correlated with PI3K-pathway activity in human prostate cancers. We propose that in PTEN-null cells, receptor-independent, SRC-dependent tyrosine-phosphorylation of PLEKHS1 creates positive-feedback that escapes homeostasis, drives PIP3- signalling and supports tumour progression.

cell biology↗

bioRxiv2021

T cell stiffness is enhanced upon formation of immunological synapse

T cells are activated by cognate target cells via an intimate contact, termed immunological synapse (IS). Cellular mechanical properties, especially stiffness, are essential to regulate cell functions, T cell stiffness at a subcellular level at the IS still remains largely elusive. In this work, we established an atomic force microscopy (AFM)-based elasticity mapping method on whole T cells to obtain an overview of the stiffness with a resolution of ~ 60 nm. Using Jurkat T-cells and primary human CD4+ T cells, we show that in the T cells in contact with functionalized surfaces, the lamellipodia are stiffer than the cell body. Upon IS formation, T cell stiffness is substantially enhanced both at the lamellipodia and in cell body. Chelation of intracellular Ca2+ abolishes IS-induced stiffening at the lamellipodia but has no influence on cell body-stiffening, suggesting different regulatory mechanism of IS-induced stiffening between the lamellipodia and the cell body.

biophysics↗

bioRxiv2020

Cortical network mechanisms of response inhibition

Both the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (pre-SMA) are crucial for successful response inhibition. However, the particular functional roles of those two regions have been controversially debated for more than a decade now. It is unclear whether the rIFG directly initiates stopping or serves an attentional function, whereas the stopping is triggered by the pre-SMA. The current multimodal MEG/fMRI study sought to clarify the role and temporal activation order of both regions in response inhibition using a selective stopping task. This task dissociates inhibitory from attentional processes. Our results reliably reveal a temporal precedence of rIFG over pre-SMA. Moreover, connectivity during response inhibition is directed from rIFG to pre-SMA and predicts stopping performance. Response inhibition is implemented via beta-band oscillations. Our findings support the hypothesis that response inhibition is initiated by the rIFG as a form of attention-independent top-down control.

neuroscience↗

bioRxiv2019

A Mechanism for Neurofilament Transport Acceleration through Nodes of Ranvier

AbstractNeurofilaments are abundant space-filling cytoskeletal polymers in axons that are transported along microtubule tracks. Neurofilament transport is accelerated at nodes of Ranvier, where axons are locally constricted. Strikingly, these constrictions are accompanied by a sharp decrease in neurofilament number but no decrease in microtubule number, bringing neurofilaments closer to their microtubule tracks. We hypothesize this leads to an increase in the proportion of the time that the filaments spend moving and that this can explain the local acceleration. To test this, we developed a stochastic model of neurofilament transport that tracks their number, kinetic state and proximity to nearby microtubules in space and time. The model assumes that the probability of a neurofilament moving is dependent on its distance from the nearest available microtubule track. Taking into account experimentally reported numbers and densities for neurofilaments and microtubules in nodes and internodes, we show that the model is sufficient to explain the local acceleration of neurofilaments across nodes of Ranvier. This suggests that proximity to microtubule tracks may be a key regulator of neurofilament transport in axons, which has implications for the mechanism of neurofilament accumulation in development and disease.

neuroscience↗

bioRxiv2019

Stochastic Models of Polymerization Based Axonal Actin Transport

Pulse-chase and radio-labeling studies have shown that actin is transported in bulk along the axon at rates consistent with slow axonal transport. In a recent paper, using a combination of live cell imaging, super resolution microscopy and computational modeling, we proposed that biased polymerization of metastable actin fibers (actin trails) along the axon shaft forms the molecular basis of bulk actin transport. The proposed mechanism is unusual, and can be best described as molecular hitch hiking, where G-actin molecules are intermittently incorporated into actin fibers which grow preferably in anterograde direction giving rise to directed transport, released after the fibers collapse only to be incorporated into another fiber. In this paper, we use our computational model to make additional predictions that can be tested experimentally to further scrutinize our proposed mechanism for bulk actin transport. In the previous paper the caliber of our model axon, the density of the actin nucleation sites to form the metastable actin fibers, the length distribution of the actin trails and their growth rate were adapted to the biologic axons used for measurements. Here we predict how the transport rate will change with axon caliber, density of nucleation sites, nucleation rates and trail lengths. We also discuss why a simple diffusion-based transport mechanism can not explain bulk actin transport.

neuroscience↗

bioRxiv2017

Processive movement of actin by biased polymerization: a new paradigm of axonal transport

Classic pulse-chase studies have shown that actin is conveyed in slow axonal transport, but the mechanistic basis for this movement is unknown. Recently, we reported that axonal actin was surprisingly dynamic, with focal assembly/dis-assembly events (\"hotspots\") and elongating polymers along the axon-shaft (\"trails\"). Using a combination of live imaging, super-resolution microscopy, and modeling, here we explore how these axonal actin dynamics can lead to processive transport. We found abundant actin nucleation, along with a slow, anterogradely-biased flow of actin in axon-shafts. Starting with first principles of monomer/filament assembly - and incorporating imaging data - we generated a quantitative model simulating axonal hotspots and trails. Our simulations predict that the axonal actin dynamics indeed lead to an anterogradely-biased flow of the population, at rates consistent with slow transport. Collectively, the data point to a surprising scenario where local assembly and biased polymerization generate the slow axonal transport of actin. This mechanism is distinct from polymer-sliding, and seems well suited to convey highly dynamic cytoskeletal cargoes.\n\nAcknowledgementsThis work was supported by an NIH grant to SR (R01NS075233). The authors thank Stephanie Gupton (UNC) for the Mena/Vasp constructs.

neuroscience↗