Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex.
ten Klooster JP, Jansen M, Yuan J, Oorschot V, Begthel H, Di Giacomo V, Colland F, de Koning J, Maurice MM, Hornbeck P, Clevers H
Hubrecht Institute, KNAW and University Medical Centre, Utrecht, The Netherlands.
The human Lkb1 kinase, encoded by the ortholog of the invertebrate Par4 polarity gene, is mutated in Peutz-Jeghers cancer syndrome. Lkb1 activity requires complex formation with the pseudokinase Strad and the adaptor protein Mo25. The complex can induce complete polarization in a single isolated intestinal epithelial cell. We describe an interaction between Mo25alpha and a human serine [?]/threonine kinase termed Mst4. A homologous interaction occurs in the yeast Schizosaccharomyces pombe in the control of polar tip growth. Human Mst4 translocates from the Golgi to the subapical membrane compartment upon activation of Lkb1. Inhibition of Mst4 activity inhibits Lkb1-induced brush border formation, whereas other aspects of polarity such as the formation of lateral junctions remain unaffected. As an essential event in brush border formation, Mst4 phosphorylates the regulatory T567 residue of Ezrin. These data define a brush border induction pathway downstream of the Lkb1/Strad/Mo25 polarization complex, yet separate from other polarity events.
Dev. Cell (2009)
PMID: 19386264 Fulltext – Related articles – Download citation
Use of docking peptides to design modular substrates with high efficiency for mitogen-activated protein kinase extracellular signal-regulated kinase.
Fernandes N1, Bailey DE, Vanvranken DL, Allbritton NL.
The mitogen-activated protein kinase extracellular regulated kinase (ERK) plays a key role in the regulation of cellular proliferation. Mutations in the ERK cascade occur in 30% of malignant tumors. Thus understanding how the kinase identifies its cognate substrates as well as monitoring the activity of ERK is central to cancer research and therapeutic development. ERK binds to its protein targets, both downstream substrates and upstream activators, via a binding site distinct from the catalytic site of ERK. The substrate sequences that bind, or dock, to these sites on ERK influence the efficiency of phosphorylation. For this reason, simple peptide substrates containing only phosphorylation sequences typically possess low efficiencies for ERK. Appending short docking peptides derived from full-length protein substrates and activators of ERK to a phosphorylation sequence increased the affinity of ERK for the phosphorylation sequence by as much as 200-fold while only slightly diminishing the maximal velocity of the reaction. The efficiency of the phosphorylation reaction was increased by up to 150-fold, while the specificity of the substrate for ERK was preserved. Simple modular peptide substrates, which can be easily tailored to possess high phosphorylation efficiencies, will enhance our understanding of the regulation of ERK and provide a tool for the development of new kinase assays.
PMID: 17918909 [PubMed – indexed for MEDLINE] PMCID: PMC2597387 Free PMC Article