Michael Sela

Bio: Michael Sela is an academic researcher from Weizmann Institute of Science. The author has contributed to research in topics: Antigen & Antibody. The author has an hindex of 86, co-authored 539 publications receiving 28065 citations. Previous affiliations of Michael Sela include Stanford University & Israel Institute for Biological Research.

The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain

Abstract: In this article, Anfinsen, Haber, Sela, and White reported that there existed a considerable lag phase before enzymatic activity appeared after the sample of bovine pancreatic ribonuclease was treated with mercaptoethanol in urea, during which period the sulfhydrl titer and the specific optical rotation changed along a curve similar to that of a first-order reaction. The lag in enzymatic activity in vitro often took several hours, while the same process seemed to take only a few minutes in vivo. This discrepancy eventually led to the discovery of an enzyme system in the endoplasmic reticulum of cells that catalyzes the disulfide interchange reaction, and subsequently, the rapid formation of the correct, native disulfide pairing in relatively short order.

Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.

Abstract: The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.

Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors.

Abstract: Carcinoma, cancer of epithelial cells, is a major cause of morbidity and mortality in Western societies. Clonal fixation and propagation of oncogenic genetic changes, sporadically accumulating in epithelial cells, depend on growth factors and their surface receptors. One of the large families of receptors is that of the ErbB tyrosine kinases, which bind multiple neuregulins and other epidermal growth factor-like molecules. Certain ErbB members and their ligands are involved in human cancers of various origins. However, most of the clinical data relate to ErbB-2, a protein whose overexpression in subsets of carcinomas can predict poor prognosis. Although no ligand has so far been assigned to ErbB-2, recent biochemical evidence implies that this oncoprotein operates as a shared receptor subunit of other ErbBs. Several biochemical attributes enable ErbB-2 to act as an epithelial cell amplifier of stroma-derived growth factor signals: It delays ligand dissociation, enhances coupling to the mitogen-activated protein kinase pathway, and impedes the rate of receptor downregulation. The realization that ErbB-2 is a master regulator of a signaling network that drives epithelial cell proliferation identifies this protein as a target for cancer therapy. Indeed, various ErbB-2-directed therapeutic approaches, including immunological and genetic therapies, demonstrate promising clinical potential.

The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors

Abstract: The erbB-2/HER2 oncogene is overexpressed in a significant fraction of human carcinomas of the breast, ovary, and lung in a manner that correlates with poor prognosis. Although the encoded protein resembles several receptors for growth factors, no high affinity ligand of ErbB-2 has so far been fully characterized. However, several lines of evidence have raised the possibility that ErbB-2 can augment signal transduction initiated by binding of certain growth factors to their direct receptors. Here, we contrasted these two models of ErbB-2 function: First, examination of a large series of epidermal growth factor (EGF)-like ligands and neuregulins, including virus-encoded ligands as well as related motifs derived from the precursor of EGF, failed to detect interactions with ErbB-2 when this protein was singly expressed. Second, by using antibodies that block inter-ErbB interactions and cells devoid of surface ErbB-2, we learned that signaling by all ligands examined, except those derived from the precursor of EGF, was enhanced by the oncoprotein. These results imply that ErbB-2 evolved as a shared receptor subunit of all ErbB-specific growth factors. Thus, oncogenicity of ErbB-2 in human epithelia may not rely on the existence of a specific ligand but rather on its ability to act as a coreceptor for multiple stroma-derived growth factors.

Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide.

Abstract: Three random basic copolymers of amino acids were tested for their effect on experimental allergic encephalomyelitis (EAE). One of these copolymers denoted as Cop 1, composed of alanine, glutamic acid, lysine and tyrosine, with a molecular weight of 23 000, showed a marked suppressive effect on the disease. The intravenous administration of Cop 1 in physiological saline, as late as 5 days following the challenge with the disease-inducing dose of the basic encephalitogenic protein, reduced the clinical incidence of EAE from 64% in the control group to 22%; the histological lesions were also decreased both in prevalence and in severity. The suppressive effect on the disease attained by the synthetic copolymer is of the same order of magnitude as that previously reported for the basic encephalitogen. The effect of the copolymers appears to be specific, since neither an acidic amino acid copolymer, nor unrelated basic proteins, had any protective action. On the other hand, a second batch of Cop 1 showed activity identical to that of the first batch. The potential applicability of this non-encephalitogenic and non-immunosuppressive material is discussed.

Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.

Abstract: Intact ribonucleic acid (RNA) has been prepared from tissues rich in ribonuclease such as the rat pancreas by efficient homogenization in a 4 M solution of the potent protein denaturant guanidinium thiocyanate plus 0.1 M 2-mercaptoethanol to break protein disulfide bonds. The RNA was isolated free of protein by ethanol precipitation or by sedimentation through cesium chloride. Rat pancreas RNA obtained by these means has been used as a source for the purification of alpha-amylase messenger ribonucleic acid.

Principles that Govern the Folding of Protein Chains

Abstract: Stanford Moore, William Stein, and Anfinsen were awarded the Nobel Prize in Chemistry in 1972 for \"their contribution to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease molecule.\" In his Nobel Lecture, Anfinsen provided a sketch of the rich history of research that provided the foundation for his work on protein folding and the \"Thermodynamic Hypothesis,\" and outlined potential avenues of current and future scientific exploration.