The farnesoid X receptor activates transcription independently of RXR at non-canonical response elements.

The farnesoid X receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with the retinoid X receptor (RXR). FXR is expressed as four isoforms (α1-α4) that drive transcription from IR-1 (inverted repeat-1) response elements (REs). Recently, we found that FXR isoforms α2/α4 also activate transcription from non-canonical ER-2 (everted repeat-2) REs, mediating most metabolic effects of general FXR activation.

Current perspectives on inhibitory SMAD7 in health and disease.

Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs).

RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer.

Wnt/β-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation.

Linear ubiquitination at a glance.

Ubiquitination (also known as ubiquitylation) is a post-translational modification that creates versatility in cell signalling and regulates a multitude of cellular processes. Its versatility lies in the capacity to form eight different inter-ubiquitin linkages through the seven lysine residues of ubiquitin and through its N-terminal methionine (M1). The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC), the only E3 ligase known to date that is capable of forming linear ubiquitin chains Linear ubiquitin chains are crucial modulators of innate and adaptive immune responses, and act by regulating inflammatory and cell death signalling.

Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer.

Rapidly renewing tissues such as the intestinal epithelium critically depend on the activity of small-sized stem cell populations that continuously generate new progeny to replace lost and damaged cells. The complex and tightly regulated process of intestinal homeostasis is governed by a variety of signalling pathways that balance cell proliferation and differentiation. Accumulating evidence suggests that stem cell control and daughter cell fate determination is largely dictated by the microenvironment.

The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptosis.

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity.

Interleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/interleukin-7 receptor-mediated signaling.

Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.

Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism.

Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.

LGR5+ stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5+ stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5+ stem cells.

Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine.

Unlabelled: Hyperactivation of NF-κB is a key factor in the pathophysiology of inflammatory bowel disease (IBD). We previously showed that the bile salt nuclear Farnesoid X Receptor (FXR) counter-regulates intestinal inflammation, possibly via repression of NF-κB. Here, we examine whether mutual antagonism between NF-κB and FXR exists.