Essential adaptor

Essential adaptor R eceptors keep signaling long after they are endocytosed thanks to a variety of adaptor proteins. Now, Teis et al. show on page 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 effi cient. Epidermal-specifi c 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.) identifi es a hypomorphic allele of p14 as the explanation for a familial immunodefi ciency. 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. M any cancer cells resort to ineffi cient glycoly-sis for their energy but can nevertheless survive, even when competing with their more energy-effi cient non-cancerous neighbors. One explanation , say Pelicano et al. (page 913), is that the altered metabolism can turn on an Akt survival pathway. Most cells rely primarily on the rich energy harvest that comes from oxidative phos-phorylation. But a switch to glycolysis can be induced by hypoxia, the loss of the tumor suppressor p53, expression of tumor inducers such as Myc and Ras, or mutation of certain mitochondrial enzymes. Mitochondrial mutation is particularly common in cancer cells, which are under metabolic stress that generates mutagenic oxidants. Mitochondrial DNA is a prime target for these mutations as these organelles lack many of the safegard mechanisms that prevent and repair …