Molecular Biology

R.J. Bandziulis, M.S. Swanson, G. Dreyfuss, "RNA-binding proteins as developmental regulators," Genes and Development, 3, 431-7, April 1989. Gideon Dreyfuss (University of Pennsylvania School of Medicine, Philadelphia): "Protein structural comparisons led to the discovery of identifying and unifying features shared by RNA-binding proteins of the nucleus and cytoplasm. Many of these ribonucleoproteins contain an RNA-binding domain (RBD) of approximately 90 amino acids. This amino acid sequence is conserved in organisms as diverse as yeast and humans. The most highly conserved motif within the RBD is the ribonucleoprotein consensus sequence (RNP-CS). Frequently, these proteins contain several similar RBDs. In addition, all of these proteins contain at least one unique auxiliary domain. RNP-CS proteins display binding preferences for specific RNA sequences, and several have been shown to interact with pre-mRNA sequences important for pre-mRNA processing. "The consensus motif has been used by many investigators to assign an RNA-binding function to newly discovered proteins, and has built a quick bridge between the proteins that bind to the many different RNAs along the pathway of gene expression. Several groups have identified RNP-CS proteins in Drosophila that are involved in controlling key developmental decisions through alternative pre-mRNA processing. It was not difficult to realize that this evidence pointed to RNP proteins as a new class of regulatory molecules in gene expression. "In this article we tried to provide an overview of the structural characteristics of RNP-CS proteins and speculate on how their structure may facilitate their participation in pathways that regulate development at the post- transcriptional level. We think the reason this article turned out to be of wide interest is that it brings together a variety of lines of investigation in molecular, cellular, and developmental biology and, we hope, harmonizes what were seemingly incongruous cellular events." D.P. Gearing, J.A. King, N.M. Gough, N.A. Nicola, "Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor," The EMBO Journal, 8, 3667-76, 1 December 1989. David Gearing (Immunex Corp., Seattle): "This paper is interesting for a number of reasons, not the least of which is its relevance to the current excitement over the potential clinical use of GM-CSF [granulocyte- macrophage colony-stimulating factor] in the treatment of neutropenia following chemotherapy or bone marrow transplantation. "The paper describes the isolation and characterization of a low-affinity receptor for GM-CSF from a human placental cDNA library. The cloned receptor was shown to constitute part of the high-affinity GM-CSF receptor on hematopoietic cells, since the cloned receptor is the same size as that on hematopoietic cells, and mRNA corresponding to the cDNA could be detected in hematopoietic cells. "The sequence of the receptor helped identify a new family of cytokine receptors that share the relative positions of four conserved Cys residues and the unusual sequence motif Trp-Ser-x-Trp-Ser. The family defined by these motifs has now been extended to include the receptors for interleukins 2, 3, 4, 5, 6, and 7; erythropoietin, GM-CSF; prolactin; and growth hormone. "Technically, the paper is interesting because the slide autoradiography approach used to detect the cDNA had an order of magnitude more sensitive than previous detection methods and should greatly ease the screening of plasmid-based cDNA expression libraries for receptors with low abundance mRNAs." A. Ullrich, J. Schlessinger, "Signal transduction by receptors with tyrosine kinase activity," Cell, 61, 203-12, 20 April 1990. Joseph Schlessinger (New York University Medical Center, New York): "Polypeptides such as growth factors, differentiation factors, and hormones are crucial components of the regulatory system that coordinates development of multicellular organisms. Many of these factors mediate their diverse actions by binding to and activating cell surface receptors with intrinsic protein tyrosine kinase activity. In recent years it became clear that mutations in growth factor receptors can lead to subversion of normal control mechanisms and alterations in receptor signaling. Such mutations can activate certain receptors and lead to uncontrolled cell growth and oncogenesis. Other mutations can cause receptor inactivation (for example, mutation of c-kit) and lead to developmental disorders. "Our review in Cell summarizes our studies and those of others that explore the mechanism of action of receptors with tyrosine kinase activity. In this review, we emphasize structure/ function analyses that use site-directed mutagenesis and expression in animal cells of various receptor mutants. Investigation of the properties of various chimeric receptors indicates that signal transduction across the plasma membrane is mediated by a universal mechanism. We emphasize the allosteric nature of receptors with tyrosine kinase activity and address various questions of mechanism, such as the role of receptor dimerization and the function of the catalytic kinase domain in signal transduction. An exciting topic is the recent elucidation of cytoplasmic proteins that are tyrosine phosphorylated by, and are associated with, receptors with tyrosine kinase activity such as phospholipase-Cg and GTPase activating protein. These and other as-yet-unidentified substrates may play a crucial role in control of receptor trafficking and stimulation of various early metabolic responses culminating in cell growth and differentiation."

Molecular Biology

The Scientist Staff

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