Intestinal barrier function is regulated by epithelial tight junctions, structures that control paracellular permeability. JAM-A regulates epithelial permeability through association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

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Expression of the tight junction protein junctional adhesion molecule‐A (JAM‐A) has been linked to proliferation and tumour progression. However, a direct role for JAM‐A in regulating proliferative processes has not been shown. By using complementary in vivo and in vitro approaches, we demonstrate that JAM‐A restricts intestinal epithelial cell (IEC) proliferation in a dimerization‐dependent manner, by inhibiting Akt‐dependent β‐catenin activation. Furthermore, IECs from transgenic JAM‐A−/−/β‐catenin/T‐cell factor reporter mice showed enhanced β‐catenin‐dependent transcription. Finally, inhibition of Akt reversed colonic crypt hyperproliferation in JAM‐A‐deficient mice. These data establish a new link between JAM‐A and IEC homeostasis.

X-ray crystal structures were determined of the broad-spectrum aminoglycoside-resistance A1408 16S rRNA methyltransferases KamB and NpmA, from the aminoglycoside-producer Streptoalloteichus tenebrarius and human pathogenic Escherichia coli, respectively. Consistent with their common function, both are Class I methyltransferases with additional highly conserved structural motifs that embellish the core SAM-binding fold. In overall structure, the A1408 rRNA methyltransferase were found to be most similar to a second family of Class I methyltransferases of distinct substrate specificity (m7G46 tRNA). Critical residues for A1408 rRNA methyltransferase activity were experimentally defined using protein mutagenesis and bacterial growth assays with kanamycin. Essential residues for SAM coenzyme binding and an extended protein surface that likely interacts with the 30S ribosomal subunit were thus revealed. The structures also suggest potential mechanisms of A1408 target nucleotide selection and positioning. We propose that a dynamic extended loop structure that is positioned adjacent to both the bound SAM and a functionally critical structural motif may mediate concerted conformational changes in rRNA and protein that underpin the specificity of target selection and activation of methyltransferase activity. These new structures provide important new insights that may provide a starting point for strategies to inhibit these emerging causes of pathogenic bacterial resistance to aminoglycosides.