Nuclear tyrosine kinase Rak

Details Nuclear tyrosine kinase Rak Nuclear tyrosine kinase Rak

1995-06-20

2003-03-11

Pak, Michael (Department: 1646)

Chemistry: molecular biology and microbiology

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

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

C435S193000, C435S194000, C435S320100, C435S325000, C530S300000, C530S350000, C536S023100

Reexamination Certificate

active

06531296

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a nuclear tyrosine kinase called Rak which is expressed primarily in epithelial cells. Rak has been found to be a growth inhibiting kinase. Domains of the Rak protein, and corresponding peptides, have been found to inhibit CDC2 function and therefore block the cell cycle and inhibit cell growth. Rak protein also binds to the retinoblastoma gene product in a domain distinct from the CDC2 binding region.
BACKGROUND OF THE INVENTION
The protein tyrosine kinases are a related family of proteins that play a pivotal role in signal transduction and the regulation of cellular proliferation and have been linked to tumorigenesis through both over expression and mutation. Tyrosine kinases are frequently divided into three groups: the transmembrane receptors, such as the growth factor receptors; the cytoplasmic tyrosine kinases, which are thought to act as internal transmitters of growth signals from the cell membrane; and the nuclear tyrosine kinases thought to be involved in the direct regulation of cellular division.
Prototypes of the various tyrosine kinase subfamilies include HER-2
eu, a receptor tyrosine kinase whose overexpression is a powerful predictor of poor prognosis in breast cancer; the focal adhesion kinase (FAK), a cytoplasmic kinase which plays a central role in cellular adhesion; and abl, a nuclear tyrosine kinase that is an inhibitor of cellular growth and that, when rearranged by translocation, is etiologic for chronic myelogenous leukemia.
All tyrosine kinases function as molecular “switches” for critical cellular functions such as growth, differentiation, and even cell death. These molecular switches act by physically interacting with other molecules, first by binding, which is often followed by phosphorylation, whereby the kinase adds a phosphate group to the substrate molecule. These chemical chain reactions are the connections through which a signal can be transmitted through a kinase in to the nucleus. Thus knowledge of these potentially intricate interactions may permit the targeted disruption of vital biochemical pathways of a cancer cell, or may be used as diagnostic markers of disease virulence.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a peptide having the amino acid sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln-Gly-Tyr-Ile-Pro-Ser-Asn-Tyr-Val-Ala-Glu-Asp-Arg-Ser (SEQ ID NO: 3), or the sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln (SEQ ID NO:4).
A further aspect of the present invention is a fusion protein comprising a peptide having the sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln-Gly-Tyr-Ile-Pro-Ser-Asn-Tyr-Val-Ala-Glu-Asp-Arg-Ser (SEQ ID NO: 3) or a peptide having the sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln (SEQ ID NO:4).
A further aspect of the present invention is a method of inhibiting CDC2 function within a cell by administering a peptide having the amino acid sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln-Gly-Tyr-Ile-Pro-Ser-Asn-Tyr-Val-Ala-Glu-Asp-Arg-Ser (SEQ ID NO: 3) or Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln (SEQ ID NO:4).
A further aspect of the present invention is a method of synchronizing a plurality of cells so that a majority of cells exhibit the same phase of the cell cycle, where the cells are administered a peptide of sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln-Gly-Tyr-Ile-Pro-Ser-Asn-Tyr-Val-Ala-Glu-Asp-Arg-Ser) (SEQ ID NO: 3) or sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln (SEQ ID NO:4).
A further aspect of the present invention is a method of inhibiting cell proliferation by administering to the cell a peptide of amino acid sequence Lys-Arg-Arg-Asp-Gly-Ser-Ser-Gln-Gln-Leu-Gln-Gly-Tyr-Ile-Pro-Ser-Asn-Tyr-Val-Al a-Glu-Asp-Arg-Ser (SEQ ID NO: 3); or sequence Lys-Arg-Arg-Ser-Gln-Gln-Leu-Gln (SEQ ID NO:4), the peptide administered in an effective cell proliferation inhibitory amount.


REFERENCES:
patent: 6326469 (2001-12-01), Ullrich et al.
patent: 9315201 (1993-08-01), None
Cance et al.;Rak, a Novel Nuclear Tyrosine Kinase Expresed in Epithelical Cells, Cell Growth and Differentiation5:1347 (1994).
Craven et al.;The src-related nuclear tyrosine kinase rak associates with Rb, cylin D3 and p34, AACR abstract 36: A3357 (1995).
Smith, D.B. et al. (1988) Gene 67:31-40.*
Lee, J. et al.,Cloning of FRK, a novel human intracellular Src-like tyrosine kinase encoding gene, Gene138:247-251 (1994).
Cance, W. G. et al.,Novel Protein Kinase Expressed in Human Breast Cancer, Int. J. Cancer54:571-577 (1993).

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