Biology subjects

Jaykumar, A. B.

Publications and source records attributed to Jaykumar, A. B..

5 recordsLinked to original sources

bioRxiv2024

ALMS1 KO rat: a new model of metabolic syndrome with spontaneous hypertension

ALMS1 is a protein initially associated with Alstrom syndrome. This is a rare human disorder characterized by metabolic dysfunction, hypertension, obesity and hyperinsulinemia. In addition, ALMS1 gene was linked to hypertension status in a multipoint linkage population analysis. However, the mechanisms by which ALMS1 contributes to the development of obesity, insulin resistance and other metabolic disturbances are unknown. To study the role of ALMS1 in blood pressure regulation and renal function we previously generated an ALMS1 knockout rat model, where we found these rats are hypertensive. In this study, we further characterized the ALMS1 knockout rat, and found that they exhibit most characteristics of metabolic syndrome including hypertension and higher body weight by 10-12 weeks of age. In contrast, obesity, hyperinsulinemia and vascular dysfunction manifested at around 14-16 weeks of age. Interestingly, ALMS1 KO rats developed hyperleptinemia prior to the development of obesity rapidly after weaning by 7 weeks of age, suggesting an early role for ALMS1 in the hormonal control of leptin. We also found that female ALMS1 KO rats develop severe metabolic syndrome with hypertension similar to their male counterparts, lacking any protection often associated with better cardiovascular outcomes. Therefore, ALMS1 is an essential gene for sex-and age-dependent metabolic function. The ALMS1 knockout rat provides an invaluable pre-clinical animal model that recapitulates most symptoms present in patients and allows the study of new drugs and mechanisms that cause metabolic syndrome.

physiology↗

bioRxiv2024

SMURF1/2 are novel regulators of WNK1 stability

Angiogenesis is essential for remodeling and repairing existing vessels, and this process requires signaling pathways including those controlled by transforming growth factor beta (TGF-{beta}). We have previously reported crosstalk between TGF-{beta} and the protein kinase With No lysine (K) 1 (WNK1). Homozygous disruption of the gene encoding WNK1 results in lethality in mice near embryonic day E12 due to impaired angiogenesis and this defect can be rescued by endothelial-specific expression of an activated form of the WNK1 substrate kinase Oxidative Stress-Responsive 1 (OSR1). However, molecular processes regulated via a collaboration between TGF-{beta} and WNK1/OSR1 are not well understood. Here we show that WNK1 interacts with the E3 ubiquitin ligases SMURF1/2. In addition, we discovered that WNK1 regulates SMURF1/2 protein stability and vice versa. We also demonstrate that WNK1 activity regulates TGF-{beta} receptor levels, in turn, controlling TGF-{beta} signaling.

biochemistry↗

bioRxiv2024

Predictive and Experimental Motif Interaction Analysis Identifies Functions of the WNK-OSR1/SPAK Pathway

The WNK-OSR1/SPAK protein kinase signaling pathway regulates ion homeostasis and cell volume, but its other functions are poorly understood. To uncover undefined signaling functions of the pathway we analyzed the binding specificity of the conserved C-terminal (CCT) domains of OSR1 and SPAK to find all possible interaction motifs in human proteins. These kinases bind the core consensus sequences R-F-x-V/I and R-x-F-x-V/I. Motifs were ranked based on sequence, conservation, cellular localization, and solvent accessibility. Out of nearly 3,700 motifs identified, 90% of previously published motifs were within the top 2% of those predicted. Selected candidates (TSC22D1, CAVIN1, ATG9A, NOS3, ARHGEF5) were tested. Upstream kinases WNKs 1-4 and their close relatives, the pseudokinases NRBP1/2, contain CCT-like domains as well. We identified additional distinct motif variants lacking the conserved arginine previously thought to be required, and found that the NRBP1 CCT-like domain binds TSC22D1 via the same motif as OSR1 and SPAK. Our results further highlight the rich and diverse functionality of CCT and CCT-like domains in connecting WNK signaling to cellular processes.

biochemistry↗

bioRxiv2024

WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling

Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary cortical neurons and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.

animal behavior and cognition↗

bioRxiv2021

WNK1 Enhances Migration and Invasion in Breast Cancer Models

Metastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

cancer biology↗