Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-09-09
2003-03-04
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007210, C435S007230, C435S004000, C424S009200, C436S063000, C436S064000, C436S518000
Reexamination Certificate
active
06528270
ABSTRACT:
1. INTRODUCTION
The present invention relates to compositions and methods for the prevention and treatment of cell proliferative disorders wherein a protein tyrosine kinase or protein tyrosine phosphatase capable of complexing with a member of the SH2- and/or SH3-containing family of adaptor proteins is involved. This invention is based, in part, on the surprising discovery that the adaptor protein, GRB-2, binds the intracellular BCR-ABL tyrosine kinase product in vivo and is necessary for the activation of the oncogenic potential of the BCR-ABL product and that disruption of the signaling capability of GRB-2 can reverse the transformed phenotype of cells and reduce tumor growth in animals. The present invention further relates to protein tyrosine kinase/adaptor protein complexes and the uses of these complexes for the identification of agents capable of disrupting the interaction between the members of such complexes.
2. BACKGROUND
2.1. Protein Phosphorylation and Signal Transduction
Cells rely, to a great extent, on extracellular molecules as a means by which to receive stimuli from their immediate environment. These extracellular signals are essential for the correct-regulation of such diverse cellular processes as differentiation, contractility, secretion, cell division, contact inhibition, and metabolism. The extracellular molecules, which can include, for example, hormones, growth factors, lymphokines, or neurotransmitters, act as ligands that bind specific cell surface receptors. The binding of these ligands to their receptors triggers a cascade of reactions that brings about both the amplification of the original stimulus and the coordinate regulation of the separate cellular processes mentioned above. In addition to normal cellular processes, receptors and their extracellular ligands may be involved in abnormal or potentially deleterious processes such as virus-receptor interaction, inflammation, and cellular transformation to a cancerous state.
A central feature of this process, referred to as signal transduction (for recent reviews, see Posada et al., 1992,
Mol. Biol. Cell
3:583-592; Hardie, D. G., 1990,
Symp. Soc. Exp. Biol.
44:241-255), is the reversible phosphorylation of certain proteins.
The phosphorylation or dephosphorylation of amino acid residues triggers conformational changes in regulated proteins that alter their biological properties. Proteins are phosphorylated by protein kinases and are dephosphorylated by protein phosphatases. Protein kinases and phosphatases are classified according to the amino acid residues they act on, with one class being serine-threonine kinases and phosphatases (reviewed in Scott et al., 1992, 2:289-295), which act on serine and threonine residues, and the other class being the tyrosine kinases and phosphatases (reviewed in Fischer et al., 1991,
Science
253:401-406; Schlessinger et al., 1992,
Neuron
9:383-391; Ullrich et al., 1990,
Cell
61:203-212), which act on tyrosine residues. Phosphorylation is a dynamic process involving competing phosphorylation and dephosphorylation reactions, and the level of phosphorylation at any given instant reflects the relative. activities, at that instant, of the protein kinases and phosphatases that catalyze these reactions.
While the majority of protein phosphorylation occurs at serine and threonine amino acid residues, phosphorylation at tyrosine residues also occurs, and has begun to attract a great deal of interest since the discovery that many oncogene products and growth factor receptors possess intrinsic protein tyrosine kinase activity. The importance of protein tyrosine phosphorylation in growth factor signal transduction, cell cycle progression and neoplastic transformation is now well established (Cantley et al., 1991,
Cell
64:281-302; Hunter T., 1991,
Cell
64:249-270; Nurse, 1990,
Nature
344:503-508; Schlessinger et al., 1992,
Neuron
9:383-391; Ullrich et al., 1990,
Cell
61:203-212). Subversion of normal growth control pathways leading to oncogenesis has been shown to be caused by activation or overexpression of protein tyrosine kinases which constitute a large group of dominant oncogenic proteins (reviewed in Hunter, T., 1991,
Cell
64:249-270).
2.2. Protein Tyrosine Kinases
Protein tyrosine kinases comprise a large family of proteins, including many growth factor receptors and potential oncogenes, which share ancestry with, but nonetheless differ from, serine/threonine-specific protein kinases (Hanks et al., 1988,
Science
241:42-52). The protein kinases may further be defined as being receptors or non-receptors.
Receptor-type protein tyrosine kinases, which have a transmembrane topology have been studied extensively. The binding of a specific ligand to the extracellular domain of a receptor protein tyrosine kinase is thought to induce receptor dimerization and phosphorylation of their own tyrosine residues. Individual phosphotyrosine residues of the cytoplasmic domains of receptors may serve as specific binding sites that interact with a host of cytoplasmic signalling molecules, thereby activating various signal transduction pathways (Ullrich et al., 1990,
Cell
61:203-212).
The intracellular, cytoplasmic, non-receptor protein tyrosine kinases may be broadly defined as those protein tyrosine kinases which do not contain a hydrophobic, transmembrane domain. Within this broad classification, one can divide the known cytoplasmic protein tyrosine kinases into four distinct morphotypes: the SRC family (Martinez et al., 1987,
Science
237:411-414; Sukegawa et al., 1987,
Mol. Cell. Biol.
7:41-47; Yamanishi et al., 1987, 7:237-243; Marth et al., 1985,
Cell
43:393-404; Dymecki et al., 1990,
Science
247:332-336), the FES family (Ruebroek et al., 1985,
EMBO J.
4:2897-2903; Hao et al., 1989,
Mol. Cell. Biol.
9:1587-1593), the ABL family (Shtivelman et al., 1986,
Cell
47:277-284; Kruh et al., 1986,
Science
234:1545-1548), and the JAK family. While distinct in their overall molecular structure, each of the members of these morphotypic families of cytoplasmic protein tyrosine kinases share non-catalytic domains in addition to sharing their catalytic kinase domains. Such non-catalytic domains are the SH2 (SRC homology domain 2; Sadowski et al.,
Mol. Cell. Biol.
6: 4396-4408; Koch et al., 1991,
Science
252:668-674) domains and SH3 domains (Mayer et al., 1988,
Nature
332:269-272). Non-catalytic domains are thought to be important in the regulation of protein-protein interactions during signal transduction (Pawson et al., 1992,
Cell
71:359-362).
While the metabolic roles of cytoplasmic protein tyrosine kinases are less well understood than that of the receptor-type protein tyrosine kinases, significant progress has been made in elucidating some of the processes in which this class of molecules is involved. For example, lck and fyn, members of the src family, have been shown to interact with CD4/CD8 and the T cell receptor complex, and are thus implicated in T cell activation, (Veillette et al., 1992,
TIG
8:61-66). Certain cytoplasmic protein tyrosine kinases have been linked to certain phases of the cell cycle (Morgan et al., 1989,
Cell
57:775-786; Kipreos et al., 1990,
Science
248: 217-220; Weaver et al., 1991,
Mol. Cell. Biol.
11:4415-4422). Cytoplasmic protein tyrosine kinases have been implicated in neuronal development (Maness, P., 1992,
Dev. Neurosci.
14:257-270). Deregulation of kinase activity through mutation or overexpression is a well-established mechanism underlying cell transformation (Hunter et al., 1985, supra; Ullrich et al., supra).
2.3. G-Proteins and Signal Transduction
Guanine-nucleotide-binding proteins, (G-proteins; Simon et al., 1991,
Science
252:802-808; Kaziro et al., 1991,
Ann. Rev. Biochem.
60:349-400) such as Ras (for review, see Lowy et al., 1993,
Ann Rev. Biochem.
62:851-891), play an essential role in the transmission of mitogenic signals from receptor tyrosine kinases. Taking Ras as an example, the activation of receptor tyrosine kinases by ligand binding results in the accumulation of the active GTP bou
Gishizky Mikhail L.
Pendergast Ann Marie
Schlessinger Joseph
Caputa Anthony C.
Foley & Lardner
Hunt Jennifer
Sugen Inc.
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