ArfGAP1 inhibits mTORC1 lysosomal localization and activation

The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid‐deficient conditions is not completely understood. Here, we identify ADP‐ribosylation factor GTPase‐activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature‐sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.     

Design of Tripeptides as a Competitive Inhibitor for HMG-CoA Reductase

International Journal of Peptide Research and Therapeutics - This study presents a simple approach in design of tripeptides as a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase...     

A compensation of angular displacements of the hip joints and lumbosacral spine between subjects with and without idiopathic low back pain during squatting

Low back pain (LBP) is one of the most common symptoms reported in adults. However, the contribution of postural control on the lumbar spine and hips during squatting has not been carefully investigated in individuals with LBP. The aim of this study was to compare three-dimensional kinematic changes of the lumbar spine and hips between subjects with and without idiopathic chronic LBP during squatting activities. In total, 30 subjects enrolled in the study (15 control subjects and 15 subjects with idiopathic chronic LBP). All participants were asked to perform squatting activities five times repeatedly while holding a load of 2 kg in a basket. The outcome measures included the Oswestry Disability Index (ODI) and kinematic angular displacement for the hips and lumbar spine. The LBP group demonstrated increased range of motion (ROM) in flexion of the dominant (T = ?2.14, p = 0.03) and non-dominant (T = ?2.11, p = 0.03) hips during squatting. The lumbar spine flexion ROM significantly decreased (T = 2.20, p = 0.03). The kinematic changes demonstrated interactions with region × group (F = 5.56, p = 0.02), plane × group (F = 4.36, p = 0.04), and region × plane (F = 2292.47, p = 0.001). The ODI level demonstrated significant interaction on combined effects of body region and plane (F = 4.91, p = 0.03). Therefore, the LBP group utilized a compensation strategy to increase hip flexion with a stiffened lumbar spine in the sagittal plane during squatting. This compensatory kinematic strategy could apply to clinical management used to enhance lumbar spine flexibility in subjects with idiopathic chronic LBP.     

SMURF1 Plays a role in EGF-induced breast cancer cell migration and invasion

Epidermal growth factor (EGF) is a well-known growth factor that induces cancer cell migration and invasion. Previous studies have shown that SMAD ubiquitination regulatory factor 1 (SMURF1), an E3 ubiquitin ligase, regulates cell motility by inducing RhoA degradation. Therefore, we examined the role of SMURF1 in EGF-induced cell migration and invasion using MDA-MB-231 cells, a human breast cancer cell line. EGF increased SMURF1 expression at both the mRNA and protein levels. All ErbB family members were expressed in MDA-MB-231 cells and receptor tyrosine kinase inhibitors specific for the EGF receptor (EGFR) or ErbB2 blocked the EGF-mediated induction of SMURF1 expression. Within the signaling pathways examined, ERK1/2 and protein kinase C activity were required for EGF-induced SMURF1 expression. The overexpression of constitutively active MEK1 increased the SMURF1 to levels similar to those induced by EGF. SMURF1 induction by EGF treatment or by the overexpression of MEK1 or SMURF1 resulted in enhanced cell migration and invasion, whereas SMURF1 knockdown suppressed EGF- or MEK1-induced cell migration and invasion. EGF treatment or SMURF1 overexpression decreased the endogenous RhoA protein levels. The overexpression of constitutively active RhoA prevented EGF- or SMURF1-induced cell migration and invasion. These results suggest that EGFinduced SMURF1 plays a role in breast cancer cell migration and invasion through the downregulation of RhoA.     

Comparative proteomic analysis of cysteine oxidation in colorectal cancer patients

Oxidative stress promotes damage to cellular proteins, lipids, membranes and DNA, and plays a key role in the development of cancer. Reactive oxygen species disrupt redox homeostasis and promote tumor formation by initiating aberrant activation of signaling pathways that lead to tumorigenesis. We used shotgun proteomics to identify proteins containing oxidation-sensitive cysteines in tissue specimens from colorectal cancer patients. We then compared the patterns of cysteine oxidation in the membrane fractions between the tumor and non-tumor tissues. Using nano-UPLC-MS^E proteomics, we identified 31 proteins containing 37 oxidation-sensitive cysteines. These proteins were observed with IAM-binding cysteines in non-tumoral region more than tumoral region of CRC patients. Then using the Ingenuity pathway program, we evaluated the cellular canonical networks connecting those proteins. Within the networks, proteins with multiple connections were related with organ morphology, cellular metabolism, and various disorders. We have thus identified networks of proteins whose redox status is altered by oxidative stress, perhaps leading to changes in cellular functionality that promotes tumorigenesis.