Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-06-17
2002-05-14
Caputa, Anthony C. (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S024310, C435S069100, C435S320100, C435S325000
Reexamination Certificate
active
06388063
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tyrosine kinases. In particular, the invention concerns a protein we have named SAD, nucleotide sequences encoding SAD, various products and assay methods that can be used for identifying compounds useful for the diagnosis and treatment of various SAD-related diseases and conditions, for example cell proliferative disorders.
BACKGROUND OF THE INVENTION
The following description is provided to aid in understanding the invention but is not admitted to be prior art to the invention.
Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins, which enables regulation of the activity of mature proteins by altering their structure and function.
Protein kinases are one of the largest families of eukaryotic proteins with several hundred known members. These proteins share a 250-300 amino acid domain that can be subdivided into 12 distinct subdomains that comprise the common catalytic core structure. (Hanks and Hunter,
FASEB J.
9:576-595, 1995). These conserved protein motifs have recently been exploited using PCR-based cloning strategies leading to a significant expansion of the known kinases. Multiple alignment of the sequences in the catalytic domain of protein kinases and subsequent phylogenetic analysis permits their segregation into a dendrogram. In this manner, related kinases are clustered into distinct branches or subfamilies including: tyrosine kinases, cyclic-nucleotide-dependent kinases, calcium/calmodulin kinases, cyclin-dependent kinases and MAP-kinases, serine-threonine kinases and several other less defined subfamilies.
Protein kinases can also be characterized by their location within the cell. Some kinases are transmembrane receptor-type proteins capable of directly altering their catalytic activity in response to the external environment such as the binding of a ligand. Others are non-receptor-type proteins lacking any transmembrane domain. They can be found in a variety of cellular compartments from the inner surface of the cell membrane to the nucleus.
Many kinases are involved in regulatory cascades wherein their substrates may include, but are not limited to, other kinases whose activities are regulated by their phosphorylation state. Ultimately the activity of some downstream effector is modulated by phosphorylation resulting from activation of such a pathway.
The known non-receptor tyrosine kinases (NR-TKs) can be classified in to several families: the Abl family (Abl, Arg), the Jak family (Jak1, Jak2, Jak3, Tyk2), the Fps family (Fes/Fps, Fer/Flk/Tyk3), the Syk family (Syk/PTK72, Zap70), the Tec Family (Tec, Tkx, Bmx/MKK2, Btk/Emb, Itk/Tsk/Emt), the Csk family (Csk, Ctk/MKK1), the Frk family (Frk/MKK3, Brk, Srm, Iyk), the Fak family (Fak, Pyk2), the Ack family (Ack, Ack2), and the Src family, which includes the members Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. (See Bolen, Oncogene 8:2025-2031, 1993.) Some NR-TKs are expressed ubiquitously, such as Src, Abl, and Jaks 1 and 2, while others are more restricted. For example, normal Fps, Syk and Zap70 expression is restricted to a subset of hematopeoetic cells. NR-TKs are known to be involved in a variety of normal cellular processes including cell proliferation and differentiation, cytokine signaling (the Jak family) and T-cell function (Zap70).
The expression of NR-TKs has also been associated with abnormal conditions such as cancer. The first tyrosine kinase to be discovered was the v-Src oncoprotein and many others (Yes, Fgr and Lck for example) have been identified as transforming proteins. Activation of Src and Yes are among the most consistent changes in human colon tumors (Staley, et al., Proc. Annu Meet Am Assoc Cancer Res 36:A362, 1995). A need exists to identify other NR-TKs whose activity results in such unwanted conditions as cancer as the identification and association of NR-TKs with a disorder is an important step in selection of pharmaceutical compounds for appropriate treatment.
SUMMARY OF THE INVENTION
Disclosed herein is a tyrosine kinase overexpressed in cancer cells which we have named SAD. The properties of SAD are described below. The present invention concerns SAD polypeptides, nucleic acids encoding such polypeptides, cells, tissues and animals containing such nucleic acids, antibodies to the polypeptides, assays utilizing the polypeptides, and methods relating to all of the foregoing.
A first aspect of the invention features an isolated, enriched, or purified nucleic acid molecule encoding a SAD polypeptide.
By “isolated” in reference to nucleic acid it is meant a polymer of 14, 17, 21 or more nucleotides conjugated to each other, including DNA or RNA that is isolated from a natural source or that is synthesized. The isolated nucleic acid of the present invention is unique in the sense that it is not found in a pure or separated state in nature. Use of the term “isolated” indicates that a naturally occurring sequence has been removed from its normal cellular (i.e., chromosomal) environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment. The term does not imply that the sequence is the only nucleotide sequence present, but that it is essentially free (about 90-95% pure at least) of nucleotide material naturally associated with it and thus is meant to be distinguished from isolated chromosomes.
By the use of the term “enriched” in reference to nucleic acid it is meant that the specific DNA or RNA sequence constitutes a significantly higher fraction (2-5 fold) of the total DNA or RNA present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other DNA or RNA present, or by a preferential increase in the amount of the specific DNA or RNA sequence, or by a combination of the two. However, it should be noted that “enriched” does not imply that there are no other DNA or RNA sequences present, just that the relative amount of the sequence of interest has been significantly increased.
The term “significant” here is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other nucleic acids of about at least 2 fold, more preferably at least 5 to 10 fold or even more. The term also does not imply that there is no DNA or RNA from other sources. The other source DNA may, for example, comprise DNA from a yeast or bacterial genome, or a cloning vector such as pUC19. This term distinguishes the sequence from naturally occurring enrichment events, such as viral infection, or tumor type growths, in which the level of one mRNA may be naturally increased relative to other species of mRNA. That is, the term is meant to cover only those situations in which a person has intervened to elevate the proportion of the desired nucleic acid.
It is also advantageous for some purposes that a nucleotide sequence be in purified form. The term “purified” in reference to nucleic acid does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment (compared to the natural level this level should be at least 2-5 fold greater, e.g., in terms of mg/mL). Individual clones isolated from a cDNA library may be purified to electrophoretic homogeneity. The claimed DNA molecules obtained from these clones can be obtained directly from total DNA or from total RNA. The cDNA clones are not naturally occurring, but rather are preferably obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The construction of a cDNA library from mRNA involves the creation of a synthetic substance (cDNA) and pure individual cDNA clones can be isolated from th
Courtneidge Sara
Markby David
Onrust Susan
Plowman Gregory D.
Caputa Anthony C.
Foley & Lardner
Holleran Anne L.
Sugen Inc.
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