Salk Institute for Biological Studies

Abstract: xi. A6.m. x. 160 10 Eiscn. J. S. and Marder. E. (1983) SOC. New+ sci. Ahsrr. 9. 75.l II Kushncr. P. D. and Barker. D. L. (1983) J. Nercrohiol. IJ. 17-28 12 Kushner P. D. and Mavnxd. E. A. (1977) Braitl Rex I2Y. 13-28 13 Lingle. C. J. (1980) J. Camp. Physio/. 138. l87-l9Y I4 Marder. E. (1976) J. Physiol. fLondon) 257: 6.3% I5 Mardcr. E. and E&n, J. S. (1982) Sot. Neuroxi. Absfr. 8. 160 I6 Mardcr. E. and Paupardin-Tritsch. D. (lY78) J. fhy.Gof. ~Lortdot~f 280. 2 I-3-236 I7 Maynard. D. M. (1972) Am. NY Acad. Sci. 193. 5%72 18 Miller, J. P. and Selverston, A. I. (1982) Res. 223.19-38 J. Neurophysiol. 48. 137U-1391 28 Russell. D. F. and Hartline. D. K. (1982) 19 Miller, J. P. and Sclverston. A. I. (1982) 1. Neurophysiol. 48. 914937

Abstract: A fluid mosaic model is presented for the gross organization and structure of the proteins and lipids of biological membranes. The model is consistent with the restrictions imposed by thermodynamics. In this model, the proteins that are integral to the membrane are a heterogeneous set of globular molecules, each arranged in an amphipathic structure, that is, with the ionic and highly polar groups protruding from the membrane into the aqueous phase, and the nonpolar groups largely buried in the hydrophobic interior of the membrane. These globular molecules are partially embedded in a matrix of phospholipid. The bulk of the phospholipid is organized as a discontinuous, fluid bilayer, although a small fraction of the lipid may interact specifically with the membrane proteins. The fluid mosaic structure is therefore formally analogous to a two-dimensional oriented solution of integral proteins (or lipoproteins) in the viscous phospholipid bilayer solvent. Recent experiments with a wide variety of techniqes and several different membrane systems are described, all of which abet consistent with, and add much detail to, the fluid mosaic model. It therefore seems appropriate to suggest possible mechanisms for various membrane functions and membrane-mediated phenomena in the light of the model. As examples, experimentally testable mechanisms are suggested for cell surface changes in malignant transformation, and for cooperative effects exhibited in the interactions of membranes with some specific ligands. Note added in proof: Since this article was written, we have obtained electron microscopic evidence (69) that the concanavalin A binding sites on the membranes of SV40 virus-transformed mouse fibroblasts (3T3 cells) are more clustered than the sites on the membranes of normal cells, as predicted by the hypothesis represented in Fig. 7B. T-here has also appeared a study by Taylor et al. (70) showing the remarkable effects produced on lymphocytes by the addition of antibodies directed to their surface immunoglobulin molecules. The antibodies induce a redistribution and pinocytosis of these surface immunoglobulins, so that within about 30 minutes at 37 degrees C the surface immunoglobulins are completely swept out of the membrane. These effects do not occur, however, if the bivalent antibodies are replaced by their univalent Fab fragments or if the antibody experiments are carried out at 0 degrees C instead of 37 degrees C. These and related results strongly indicate that the bivalent antibodies produce an aggregation of the surface immunoglobulin molecules in the plane of the membrane, which can occur only if the immunoglobulin molecules are free to diffuse in the membrane. This aggregation then appears to trigger off the pinocytosis of the membrane components by some unknown mechanism. Such membrane transformations may be of crucial importance in the induction of an antibody response to an antigen, as well as iv other processes of cell differentiation.

Abstract: Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.

Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

Abstract: David J. Mangelsdorf,’ Carl Thummel,2 Miguel Beato,3 Peter Herrlich,4 Giinther Schiitq5 Kazuhiko Umesono,6 Bruce Blumberg,’ Philippe Kastner,’ Manuel Mark,* Pierre Chambon,8 and Ronald M. Evan&‘* ‘Howard Hughes Medical Institute University of Texas Southwestern Medical Center Dallas, Texas 75235-9050 *Howard Hughes Medical Institute University of Utah Salt Lake City, Utah 84112 31nstutut fiir Molekularbiologie und Tumorforschung 35037 Marburg Federal Republic of Germany 4Forschungszentrum Karlsruhe lnstitut Genetik 76021 Karlsruhe Federal Republic of Germany 5Deutsches Krebsforschungszentrum 69120 Heidelberg Federal Republic of Germany GAdvanced Institute of Science and Technology Graduate School of Biological Sciences Nara 630-01 Japan ‘The Salk Institute for Biological Studies La Jolla, California 92037-5800 Blnstitut de Genetique et de Biologie Moleculaire et Cellulaire Centre National de la Recherche Scientifique lnstitut National de la Sante et de la Recherche M6dicale 67404 lllkirch Cedex Strasbourg France gHoward Hughes Medical Institute The Salk Institute for Biological Studies La Jolla, California 92037-5800