Signal transduction

About: Signal transduction is a research topic. Over the lifetime, 122628 publications have been published within this topic receiving 8209258 citations. The topic is also known as: GO:0007165.

Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation

Abstract: The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.

Bone morphogenetic proteins, their antagonists, and the skeleton.

Abstract: Skeletal homeostasis is determined by systemic hormones and local factors. Bone morphogenetic proteins (BMP) are unique because they induce the differentiation of mesenchymal cells toward cells of the osteoblastic lineage and also enhance the differentiated function of the osteoblast. However, the activity of BMPs needs to be tempered by intracellular and extracellular antagonists. BMPs bind to specific receptors and signal by phosphorylating the cytoplasmic proteins mothers against decapentaplegic (Smad) 1 and 5, which form heterodimers with Smad 4, and after nuclear translocation regulate transcription. BMP antagonists can be categorized as pseudoreceptors that compete with signaling receptors, inhibitory Smads that block signaling, intracellular binding proteins that bind Smad 1 and 5, and factors that induce ubiquitination and proteolysis of signaling Smads. In addition, a large number of extracellular proteins that bind BMPs and prevent their binding to signaling receptors have emerged. They are the ...

STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.

Abstract: As part of the innate immune response, various pattern recognition receptors, such as Toll-like receptor 3 (TLR3) and TLR4, activate the kinase TBK1, which phosphorylates the transcription factor IRF3, leading to the production of type I interferons (IFNs). Tanaka and Chen used an in vitro reconstitution system to investigate the mechanism by which TBK1-mediated IRF3 activation occurs in response to the presence of cytosolic DNA from viruses or bacteria, a response that depends on the adaptor protein STING (see the Perspective by Bowie). Cytosolic DNA triggered the sequential recruitment of TBK1 and IRF3 to STING, which acted as a scaffold upon which TBK1 phosphorylated both STING and IRF3. Given that not all pattern recognition receptors that stimulate TBK1 lead to IRF3 activation, the authors suggest that STING specifies the activation of IRF3 by a subset of receptors that activate both TBK1 and STING—and that other adaptor proteins may fulfill similar roles in other innate immune pathways.