WDR26: A novel Gβ‐like protein, suppresses MAPK signaling pathway

Abstract

WD40 repeat proteins play important roles in a variety of cellular functions, including cell growth, proliferation, apoptosis, and intracellular signal transduction. Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes in cell signal transduction connecting cell-surface receptors to critical regulatory targets within cells and control cell survival, adaptation, and proliferation. Previous studies revealed that G-protein coupled receptors (GPCRs) play important roles in the signal transduction from extracellular stimuli to MAPKs and the WD40-containing Gbeta proteins as well as Gbeta-like proteins are involved in the stimulation and regulation of the MAPK signaling pathways. Here we report the identification and characterization of a novel human WD40 repeat protein, WD40 repeat protein 26 (WDR26). The cDNA of WDR26 is 3,729 bp, encoding a Gbeta-like protein of 514 amino acids in the cytoplasm. The protein is highly conserved in evolution across different species from yeast, Drosophila, mouse, to human. Northern blot analysis indicates that WDR26 is expressed in most of the examined human tissues, especially at a high level in skeletal muscle. Overexpression of WDR26 in the cell inhibits the transcriptional activities of ETS proteins, ELK-1 and c-fos serum response element (SRE), mediated by MEKK1. These results suggest that WDR26 may act as a negative regulator in MAPK signaling pathway and play an important role in cell signal transduction.

The WD40 Repeat Protein WDR26 Binds Gβγ and Promotes Gβγ-dependent Signal Transduction and Leukocyte Migration

“…Excessive G␤␥ signaling has been implicated in diverse pathological conditions, such as heart failure (57, 58), inflammation (59), and tumor cell growth/metastasis (36, 60, 61). Given that WDR26 is ubiquitously expressed (33), future studies will be important to determine whether WDR26 contributes to the regulation of G␤␥ signaling in other normal cellular processes and if its dysregulation contributes to aberrant G␤␥ signaling and disease.…”

“…It is ubiquitously expressed and has been shown to protect neuronal cells from hydrogen peroxide-induced cell death (32,33). Overexpression of the C-terminal fragment of WDR26 inhibited MEKK1-mediated transcription activities in COS7 cells (33), but promoted proliferation of a rat cardiomyoblast cell line (34).…”

WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

“…WDR26 has been implicated in the regulation of the MAPK signaling pathway, neuronal and cardiomyoblast cell proliferation, and apoptosis (17)(18)(19)(20). Down-regulation of WDR26 alleviated G␤␥-mediated PI3K and PLC␤ activation and leukocyte chemotaxis, indicating that WDR26 is required for efficacious G␤␥ signaling in leukocytes (16).…”

Gene expression profiling on acute rejected transplant kidneys with microarray

“…HSP70 can promote dendritic cell maturation and stimulate secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1β, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and regulated upon activation, normal T cells expressed and secreted (RANTES), most of these cytokines had been demonstrated to be critical genes for allograft rejection [11] . The expression level of heat shock protein 70 is also increased in native and heterotopically transplanted rat hearts [12] .…”

“…Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity [11] . HSP70 can promote dendritic cell maturation and stimulate secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1β, tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and regulated upon activation, normal T cells expressed and secreted (RANTES), most of these cytokines had been demonstrated to be critical genes for allograft rejection [11] .…”