Biology subjects

Sung, J. H.

Publications and source records attributed to Sung, J. H..

3 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↗

bioRxiv2022

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimers disease, wherein the {varepsilon}4 allele confers a dramatically elevated risk compared to the more common {varepsilon}3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without A{beta} accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human A{beta}1-42. In male ApoE3-TR mice, introduction of A{beta} caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of A{beta} had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry an APOE {varepsilon}4 allele. The fact that ApoE4 generally failed to exacerbate the effects of A{beta} on glucose further highlights the growing distinction between the glycemic effects of A{beta} versus those of peripheral insulin resistance.

physiology↗

bioRxiv2022

Tyrosine phosphorylation of mitofusin 2 regulates endoplasmic reticulum-mitochondria tethering

Contact sites between the mitochondria and endoplasmic reticulum (ER) regulate the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been identified as one of the major components tethering these two organelles together. Several post-translational modifications (PTMs) of Mfn2 have been shown to modulate canonical (i.e., mitochondrial fusion) and non-canonical Mfn2 functions, such as mitophagy and activation of ER stress signaling. However, there is little information about whether any PTMs can regulate mitochondrial and ER tethering. Basal tyrosine phosphorylation of Mfn2 was detected by mass spectroscopy, but it is unknown whether Mfn2 is a substrate of mitochondria-localized tyrosine kinases. Here, we show that mitochondria-localized c-Src can phosphorylate the C-terminal tail of Mfn2, which decreases the distance between the mitochondria and ER and facilitates Ca2+ transfer from the ER to mitochondria, followed by changes in ROS generation and mitochondrial bioenergetics. Our findings suggest that tyrosine phosphorylation of Mfn2 may uniquely work to fine-tune ER-mitochondrial Ca2+ transport under physiological and pathological conditions.

cell biology↗