Human NIM1 kinase

Details Human NIM1 kinase Human NIM1 kinase

2000-03-13

2002-10-01

Bansal, Geetha P. (Department: 1642)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S070100, C435S320100, C435S325000, C536S023100, C536S023500, C536S024100

Reexamination Certificate

active

06458561

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a nucleic acid molecule which encodes human NIM1 kinase and to the use of the nucleic acid molecule and the protein it encodes in the characterization, diagnosis, prevention, and treatment of brain disorders and cancers, particularly breast cancer.
BACKGROUND OF THE INVENTION
Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of molecules, biochemical and physiological mechanisms, and metabolic pathways. Despite different evolutionary pressures, the protein kinases of nematode, fly, rat, and man have common chemical and structural features and modulate the same general cellular activity. Comparisons of the nucleic acid and protein sequences from organisms where structure and/or function are known accelerate the investigation of human sequences and allow the development of model systems for testing diagnostic and therapeutic agents for human conditions, diseases, and disorders.
Protein kinases regulate many different cell proliferation, differentiation, and signaling processes by adding phosphate groups to proteins. Uncontrolled signaling has been implicated in a variety of disease conditions including inflammation, cancer, arteriosclerosis, and psoriasis. Reversible protein phosphorylation is the main strategy for controling activities of eukaryotic cells. It is estimated that more than 1000 of the 10,000 proteins active in a typical mammalian cell are phosphorylated. The high energy phosphate which drives activation is generally transferred from adenosine triphosphate (ATP) or guanosine triphosphate (GTP) to a particular protein by protein kinases and removed from that protein by protein phosphatases. Phosphorylation is roughly analogous to turning on a molecular switch, and it occurs in response to extracellular signals (mediated by such molecules as hormones, neurotransmitters, growth and differentiation factors), cell cycle checkpoints, and environmental or nutritional stresses. When the switch goes on, the appropriate protein kinase activates a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
The protein kinases comprise the largest known protein group, a superfamily of enzymes with widely varied functions and specificities. They are usually named after their substrate, their regulatory molecules, or some aspect of a mutant phenotype. With regard to substrates, the protein kinases may be roughly divided into two groups; those that phosphorylate tyrosine residues (protein tyrosine kinases, PTK) and those that phosphorylate serine or threonine residues (serine/threonine kinases, STK). A few protein kinases have dual specificity and phosphorylate both threonine and tyrosine residues.
Protein kinases may be categorized into families by the different amino acid residues (generally between 5 and 100 residues) located on either side of, or inserted into loops of, the catalytic domain. These residues allow the regulation of each kinase as it recognizes and interacts with its target protein. Almost all kinases contain a similar 250-300 amino acid catalytic domain with 11 subdomains distributed across two lobes. The N-terminal lobe, which contains subdomains I-IV, binds and orients the ATP donor molecule. The larger C terminal lobe, which contains subdomains VIA-XI, binds the protein substrate and carries out the transfer of the gamma phosphate from ATP to the hydroxyl group of a serine, threonine, or tyrosine residue. Subdomain V spans the N and C terminal lobes.
Each of the 11 subdomains contain specific residues and motifs or patterns of amino acids that are characteristic of that subdomain and are highly conserved (Hardie and Hanks (1995)
The Protein Kinase Facts Books
, Vol I, Academic Press, San Diego Calif., pp. 7-20). In particular, two protein kinase signature sequences have been identified in the kinase domain, the first containing an active site lysine residue involved in ATP binding, and the second containing an aspartate residue important for catalytic activity. If a protein is found to contain the two protein kinase signatures, the probability of that protein being a protein kinase is close to 100% (MOTIFS search program, Genetics Computer Group, Madison Wis.; Bairoch et al. (1996) Nucleic Acids Res 24:189-196).
STK Families
The second messenger dependent protein kinases primarily mediate the effects of second messengers such as cyclic AMP (cAMP), cyclic GMP, inositol triphosphate, phosphatidylinositol, 3,4,5-triphosphate, cyclic ADP ribose, arachidonic acid, diacylglycerol and calcium-calmodulin. The cyclic-AMP dependent protein kinases (PKA) are important members of the STK family. cAMP is an intracellular mediator of hormone action in all prokaryotic and animal cells that have been studied. Such hormone-induced cellular responses include thyroid hormone secretion, cortisol secretion, progesterone secretion, glycogen breakdown, bone resorption, and regulation of heart rate and force of heart muscle contraction. PKA is found in all animal cells and is thought to account for the effects of cAMP in most of these cells. Altered PKA expression is implicated in a variety of disorders and diseases including cancer, thyroid disorders, diabetes, atherosclerosis, and cardiovascular disease (Isselbacher et al. (1994)
Harrison's Principles of Internal Medicine
, McGraw-Hill, New York N.Y., pp. 416-431 and 1887).
Calcium-calmodulin (CaM) dependent protein kinases are also members of STK family. Calmodulin is a calcium receptor that mediates many calcium regulated processes by binding to target proteins in response to the binding of calcium. The principle target protein in these processes is CaM dependent protein kinases (CaMK). CaMK are involved in regulation of smooth muscle contraction, glycogen breakdown (phosphorylase kinase), and neurotransmission (CaMK I and CaMK II). CaMK I phosphorylates a variety of substrates including the neurotransmitter related proteins synapsin I and II, the gene transcription regulator, CREB, and the cystic fibrosis conductance regulator protein, CFTR (Haribabu et al. (1995)
EMBO J
14:3679-86). CaMK II also phosphorylates synapsin at different sites and controls the synthesis of catecholamines in the brain through phosphorylation and activation of tyrosine hydroxylase. Many of the CAMK are activated by phosphorylation in addition to binding to CaM. CaMK may autophosphorylate or be phosphorylated by another kinase as part of a “kinase cascade”.
Another ligand-activated protein kinase is 5′-AMP-activated protein kinase (AMPK; Dyck et al. (1996) J Biol Chem 271:17998-17803). Mammalian AMPK is a regulator of fatty acid and sterol synthesis through phosphorylation of the enzymes acetyl-CoA carboxylase and hydroxymethylglutaryl-CoA reductase and mediates responses of these pathways to cellular stresses such as heat shock and depletion of glucose and ATP. AMPK is a heterotrimeric complex comprised of a catalytic alpha subunit and two non-catalytic beta and gamma subunits that are believed to regulate the activity of the alpha subunit. Subunits of AMPK have a much wider distribution in non-lipogenic tissues such as brain, heart, spleen, and lung than expected: This distribution suggests that its role may extend beyond regulation of lipid metabolism alone.
The mitogen-activated protein kinases (MAPK) are also members of the STK family, and they regulate intracellular signaling pathways. MAPK mediate signal transduction from the cell surface to the nucleus via phosphorylation cascades. Several subgroups have been identified, and each manifests different substrate specificities and responds to distinct extracellular stimuli (Egan and Weinberg (1993) Nature 365:781-783). MAP kinase signaling pathways are present in mammalian cells as well as in yeast. The extracellular stimuli which activate mammalian pathways include epidermal growth factor, ultraviolet light, hyperosmolar medium, heat shock, e

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