Biology subjects

Sahoo, D.

Publications and source records attributed to Sahoo, D..

3 recordsLinked to original sources

bioRxiv2018

PCPE2 and SR-BI Partner to Impact Accumulation of Fat in Mice

LDL receptor knockout mice (LDLr-/-) were crossed with PCPE2 knockout mice to obtain Ldlr-/-,Pcpe2-/- mice. The rationale of these studies was to examine the effects of an extracellular matrix protein, PCPE2, on fat storage in a dyslipidemic mouse model. Male Ldlr-/-, Pcpe2-/- mice were fed a Western diet for 25 weeks and their plasma triglyceride metabolism and triglyceride storage was examined. Interestingly, visceral but not subcutaneous fat pad were smaller in diet-fed Ldlr-/-,Pcpe2-/- mice compared to controls. There was no difference in the fatty acid distribution in triglyceride and cholesteryl esters (CE) among the genotypes. Ldlr-/-, Pcpe2-/- mice have higher plasma triglyceride levels and reduced lipoprotein lipase activity. Immunoprecipitation of SR-BI from cell extracts co-precipitated PCPE2 suggesting that PCPE2 and SR-BI are tightly associated. This work also showed that in the absence of PCPE2 SR-BI does not transfer CE from HDL into the cell. These results suggest that HDL, PCPE2, SR-BI, and possibly LPL are associated in an interactome that is required for CE transport into the cell. In the absence of these interactions lipid transport is significantly disrupted.

biochemistry↗

bioRxiv2017

Guanine-nucleotide Exchange Modulator, GIV/Girdin, Serves as a Tunable Valve for Growth Factor-Stimulated Cyclic AMP Signals

Cellular levels of the versatile second messenger, cyclic-(c)AMP are regulated by the antagonistic actions of the canonical G protein[->]adenylyl cyclase pathway that is initiated by G-protein-coupled receptors (GPCRs) and by phosphodiesterases (PDEs); dysregulated cAMP signaling drives many diseases, including cancers. Recently, an alternative paradigm for cAMP signaling has emerged, in which growth factor-receptor tyrosine kinases (RTKs; e.g., EGFR) access and modulate G proteins via cytosolic guanine-nucleotide exchange modulator (GEM), GIV/Girdin; dysregulation of this pathway is frequently encountered in cancers. Here we present a comprehensive network-based compartmental model for the paradigm of GEM-dependent signaling that reveals unforeseen crosstalk and network dynamics between upstream events and the various feedback-loops that fine-tune the GEM action of GIV, and captures the experimentally determined dynamics of cAMP. The model also reveals that GIV acts a tunable control-valve within the RTK[->]cAMP pathway; hence, it modulates cAMP via mechanisms distinct from the two most-often targeted classes of cAMP modulators, GPCRs and PDEs.

systems biology↗

bioRxiv2017

Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple

Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are the Wnt/Frizzled(FZD), growth factor-receptor tyrosine kinases (RTKs), and G-proteins/GPCRs. Here we identify Daple, a modulator of trimeric G-proteins and a Dishevelled (Dvl)-binding protein as an unexpected point of convergence for all three cascades. Daple-dependent activation of Gi and enhancement of non-canonical Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but also hijacked by growth factor-RTKs to stoke tumor progression. Phosphorylation of Daple by both RTKs and non-RTKs triggers Gi activation and potentiates non-canonical Wnt signals that trigger epithelial-mesenchymal transition. In patients with colorectal cancers, concurrent upregulation of Daple and the prototype RTK, EGFR, carried poor prognosis. Thus, this work defines a novel growth factor{leftrightarrow}G-protein{leftrightarrow}Wnt crosstalk paradigm in cancer biology.

cancer biology↗