861 that the loss of p14, a protein that helps attach active MAP kinase to endosomes, results in endosome positioning defects, cell cycle problems, and death.
Mice lacking p14 died as embryos. Fibroblasts from the embryos had normal early endosomes but, compared with wild-type cells, twice as many of their late endosomes and lysosomes were located far from the nucleus, and degradation of internalized EGF receptor was half as efficient.
Epidermal-specific deletion of p14 resulted in mice that were born alive but died soon after from dehydryation. EGF receptors, normally found only in basal cell layers, were not degraded properly and were therefore expressed even in suprabasal cell layers. The mice had thin skin, apparently because of the reduced proliferation that was evident in vitro for harvested keratinocytes. This defect could not be rescued by p14 forced to localize to the plasma membrane, suggesting that the endosome localization is necessary to build a fully comptetent signaling complex.
A paper in press at Nature Medicine (authored in collaboration with Teis et al.) identifies a hypomorphic allele of p14 as the explanation for a familial immunodeficiency. Here again, endosome dynamics are disturbed, possibly because one of the motors that brings adaptor proteins to endosomes also helps localize endosomes. Teis et al. now want to see whether inhibition of endosome-localized MAP kinase signaling might be more effective against proliferation-related diseases and have fewer side effects than inhibition of all MAP kinase signaling.