The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.

The mechanisms of Hedgehog signalling and its roles in development and disease.

Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.

https://faculty.washington.edu/scottjdw/pdfs/wong_nat_rev_2004_p959.pdf

AKAP signalling complexes: focal points in space and time

Postinfectious Irritable Bowel Syndrome

https://www.gastrojournal.org/article/S0016-5085(03)00157-4/pdf

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

Tasken, Kjetil, and Einar Martin Aandahl. Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A. Physiol Rev 84: 137–167, 2004; 10.1152/physrev.00021.2003.—More than 20% of the ...

https://www.physiology.org/doi/pdf/10.1152/physrev.00021.2003

Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A

Objective. To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. Methods. Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. Results. Patients with arthritis involving >4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to <4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P = 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P < 0.02). Conclusion. The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis.

Polymorphic haplotypes of the interleukin‐10 5′ flanking region determine variable interleukin‐10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis

Centrosomal Anchoring of the Protein Kinase CK1δ Mediated by Attachment to the Large, Coiled-coil Scaffolding Protein CG-NAP/AKAP450

When the TCR binds Ag it is phosphorylated, internalized, and degraded. We wished to examine whether this process was accompanied by a specific concomitant increase in TCR mRNA levels. To do this, PBMC and a T cell clone were cultured with a series of superantigens and an alloantigen. Only T cells specifically responding to an antigenic stimulus had increased levels of TCR β-chain variable ( TCRBV )-specific mRNA. This response was apparent after 48 h, peaked around 72 h, and was still elevated after 7 days. Increased gene transcription appeared to be driven solely by Ag as specific Ag depletion prevented culture supernatants transferring this effect. The level of TCRBV mRNA elevation was not influenced by the stimulating Ag, but appeared dependent on the gene encoding the stimulated TCR. Reporter gene assays, using cloned TCRBV gene promoters, confirmed both that TCR gene transcription rises after stimulation and that basal and stimulated levels of TCR transcription vary between different TCRBV genes. These data conclusively demonstrate that there is no direct relationship between TCRBV mRNA and T cell number, and that future repertoire studies must take both factors into account.

James E. Sillibourne

Papers

Polymorphic haplotypes of the interleukin‐10 5′ flanking region determine variable interleukin‐10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis

Centrosomal Anchoring of the Protein Kinase CK1δ Mediated by Attachment to the Large, Coiled-coil Scaffolding Protein CG-NAP/AKAP450

Antigen Triggering Selectively Increases TCRBV Gene Transcription