Biology subjects

Hwang, S.-H.

Publications and source records attributed to Hwang, S.-H..

5 recordsLinked to original sources

bioRxiv2024

Loss of p21-activated kinase 4 (PAK4) suppresses pancreatic tumor progression and metastasis through regulating E-cadherin

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis with early and frequent metastasis. While p21-activated kinase 4 (PAK4) has been implicated in cell migration, and invasion, the molecular mechanisms in PDAC remain unknown. In this study, we found that PAK4 overexpression was correlated with poor survival in PDAC patients through analysis of TCGA data. PAK4-amplified PDAC cells showed enhanced mobility in contrast with wild-type. PAK4 knockdown in PAK4 amplified cells inhibited cell migration, invasion, and displacement by increased and stabilized E-cadherin, which was attributed to decreased activity of Cdc42. PAK4 knock-in in PAK4 wild-type models enhanced cell migration, invasion, and displacement by reduced E-cadherin through elevated Cdc42 activity. PAK4 bounded to E-cadherin, Cdc42, and p120ctn in immunoprecipitation. In confocal imaging, the colocalization of PAK4, E-cadherin, p120ctn, and Cdc42 was also identified. In an orthotopic PDAC mouse model, PAK4 knockdown decreased primary tumor size and occurrence of malignant ascites by activation of E-cadherin. Notably, in patients tissue specimens, inverse correlation on expression of PAK4 and E-cadherin were also shown. In conclusion, our study highlights that PAK4 promotes invasive and metastatic behavior by regulating E-cadherin in PDAC. PAK4 could be a potential therapeutic target for PDAC patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/594599v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1755a23org.highwire.dtl.DTLVardef@170b2a1org.highwire.dtl.DTLVardef@1df96edorg.highwire.dtl.DTLVardef@2dc46b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Distinct representation of cognitive flexibility and habitual stability in the primate putamen, caudate, and ventral striatum

Recent primate studies have demonstrated a functional distinction along the rostral--caudal axis of the striatum, which has challenged the conventional view that flexible adaptation and habitual action differ in processing along the medial--lateral axis. We found that neurons in the rostral putamen, caudate, and ventral striatum encode values flexibly updated for adaptive choices, rather than values stably sustained for visual habit. In the reversal value learning, rostral striatal neurons dynamically updated their value discrimination responses after value reversals, whereas, in the stable value retrieval, most did not encode the value. Notably, caudate neurons were faster to update values after reversal trials than ventral striatum neurons. Slow-learning neurons were identified selectively in the ventral striatum. In each trial, their learning speeds were similar during initial learning, suggesting a parallel value update in each striatal region. Our findings thus indicate that the rostral striatum prioritizes cognitive flexibility over habitual stability.

neuroscience↗

bioRxiv2024

Efficient value encoding through convergence of tactile and visual value information in the primate putamen

The processing of diverse sensory values by a limited number of basal ganglia neurons raises the question of whether each value is processed independently or combined as the number of neurons decreases from the cortex to downstream structures. Here, we discovered that tactile and visual values were partially converged in the primate putamen, enhancing its efficiency in encoding values while preserving modality information. Humans and monkeys performed tactile and visual value discrimination tasks. Notably, the human putamen selectively represented both tactile and visual values in fMRI scans. Single-unit electrophysiology further revealed that half of the individual neurons in the macaque putamen encoded both tactile and visual values, and the other half encoded each value separately. The bimodal value neurons enable more efficient value encoding using fewer neurons than the modality-selective value neurons. Our data suggest that the basal ganglia system uses modality convergence to efficiently encode values with limited resources.

neuroscience↗

bioRxiv2023

GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway

The orphan G protein-coupled receptor (GPCR) GPR161 is enriched in primary cilia, where it plays a central role in suppressing Hedgehog signaling1. GPR161 mutations lead to developmental defects and cancers2,3,4. The fundamental basis of how GPR161 is activated, including potential endogenous activators and pathway-relevant signal transducers, remains unclear. To elucidate GPR161 function, we determined a cryogenic-electron microscopy structure of active GPR161 bound to the heterotrimeric G protein complex Gs. This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, we identify a sterol that binds to a conserved extrahelical site adjacent to transmembrane helices 6 and 7 and stabilizes a GPR161 conformation required for Gs coupling. Mutations that prevent sterol binding to GPR161 suppress cAMP pathway activation. Surprisingly, these mutants retain the ability to suppress GLI2 transcription factor accumulation in cilia, a key function of ciliary GPR161 in Hedgehog pathway suppression. By contrast, a protein kinase A-binding site in the GPR161 C-terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how unique structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the broader role of GPR161 function in other signaling pathways.

biochemistry↗

bioRxiv2022

Identifying brain areas for tactile perception through natural finger touch with MR-compatible tactile stimulus delivery system

Primates actively touch objects with their hands to collect information. In investigations of the tactile information processes, participants should experience tactile stimuli through active touch while brain activities are monitored. Here, we developed a pneumatic tactile stimulus delivery system (pTDS) that delivers various tactile stimuli on a programmed schedule and allows tactile perception through voluntary finger touches during MRI scanning. A pneumatic actuator moved tactile blocks and placed one in a finger hole. The time when an index finger touched a tactile stimulus was detected with a photosensor, allowing analysis of the touch-elicited brain responses. The brain responses were examined while the participants actively touched braille objects presented by the pTDS. BOLD responses during tactile perception were significantly stronger in a finger touch area of the contralateral somatosensory cortex compared with that of visual perception. This pTDS enables MR study of brain mechanisms for tactile processes through natural finger touch.

neuroscience↗