Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-09-26
2002-01-15
Gambel, Phillip (Department: 1644)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100
Reexamination Certificate
active
06339148
ABSTRACT:
BACKGROUND ART
This invention relates to receptors for adhesion peptides, and more specifically to a novel receptor subunit having affinity for extracellular matrix molecules.
Multicellular organisms, such as man, have some 10
14
cells which can be divided into a minimum of fifty different types, such as blood cells and nerve cells. During the course of growth and development, cells adhere to other cells, or to extracellular materials, in specific and orderly ways. Such cell adhesion mechanisms appear to be of importance in mediating patterns of cellular growth, migration and differentiation, whereby cells develop specialized characteristics so as to function as, for example, muscle cells or liver cells. Cell adhesion mechanisms are also implicated in dedifferentiation and invasion, notably where cells lose their specialized forms and become metastasizing cancer cells.
The mechanisms underlying the interactions of cells with one another and with extracellular matrices are not fully understood, but it is thought that they are mediated by cell surface receptors which specifically recognize and bind to a cognate ligand on the surface of cells or in the extracellular matrix.
The adhesion of cells to extracellular matrices and their migration on the matrices is mediated in many cases by the binding of a cell surface receptor to an Arg-Gly-Asp containing sequence in the matrix protein, as reviewed in Ruoslahti and Pierschbacher,
Science
238:491-497 (1987). The Arg-Gly-Asp sequence is a cell attachment site at least in fibronectin, vitronectin, fibrinogen von Willibrand, thrombopondin, osteopontin, and possibly various collagens, laminin and tenascin. Despite the similarity of their cell attachment sites, these proteins can be recognized individually by their interactions with specific receptors.
The integrins are a large family of cell surface glycoprotein that mediate cell-to-cell and cell-to-matrix adhesion as described, for example, in the Ruoslahti and Pieischbacher article cited above. All known members of this family of adhesion receptors are heterodimers consisting of an &agr; and a &bgr; subunit noncovalently bound to each other. When the integrin family was first identified, integrins were grouped into three subfamilies based on the three &bgr; subunits that were initially recognized (&bgr;
1
, &bgr;
2
and &bgr;
3
). Over the past few years, the primary structures of three integrin &bgr; subunits from mammalian cells and one from Drosophila have been deduced from cDNA.
Each &agr; subunit was thought to associate uniquely with a single &bgr; subunit. Eleven distinct &agr; subunits have thus far been described. As new integrins have been identified, however, it has become clear that this grouping is not entirely satisfactory, since there are clearly more thrn three &bgr; subunits and since some &agr; subunits can associate with more than one &bgr; subunit as described, for example, in Sonnenberg et al.,
J. Biol. Chem.
265:14030-14038 (1988).
Because of the importance of integrins in mediating critical aspects of both normal and abnormal cell processes, a need exists to identify and characterize different integrins. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention relates to a substantially purified &bgr; subunit of an integrin cell surface receptor designated as &bgr;
6
. The amino acid sequence of human &bgr;
6
(SEQ ID. NO:27) is provided in FIG.
3
.
The present invention also relates to amino acid fragments specific to &bgr;
6
that have a variety of uses. The invention further relates to vectors having a gene encoding such fragments. Host cells containing such vectors are also provided. The nucleic acids encoding &bgr;
6
as well as nucleic acids that specifically hybridize with the nucleic acids encoding &bgr;
6
sequences are other aspects of the present invention.
In a further aspect, the present invention relates to a substantially purified integrin comprising &bgr;
6
bound to an &agr; subunit, particularly &agr;
V
or &agr;
F
. Methods of blocking the attachment of the &bgr;
6
-containing integrins to its ligand and of detecting the binding of such integrins to its ligand are also provided.
The present invention also relates to methods of increasing or decreasing cell adhesion in cells expressing a &bgr;
6
-containing integrin by overexpressing the integrin or by binding the integrin with a ligand, such as vitronectin.
REFERENCES:
patent: 5204445 (1993-04-01), Plow et al.
patent: 5962643 (1999-10-01), Sheppard et al.
Skolnick et al., Trends in Biotech., 18(1):34-9, Jan. 2000.*
Sheppard et al. Am Rev Resp. Disease 141: A707, May 1990.*
Sheppard et al. J. Biol. Chemistry 265: 11502 Jul. 15, 1990.*
Green, et al. The integrin B subunit. The International Journal of Biochemistry and Cell Biology, 30:179-184, 1998.*
Dixit et al. J. of Biological Chemistry, 271(42):25976-25980, Oct. 1996.*
Cheresh et al.,Cell57:59-69 (1989).
Freed et al.,EMBO J.8:2955-2965 (1989).
Holzmann et al.,Cell56:37-46 (1989).
Kajiji et al.,EMBO J.8:673-680 (1989).
Ramaswamy et al., “Cloning primary structure and properties of a novel integrin &bgr; subunit,”EMBO J.9(5):1561-1568 (1990).
Sheppard et al., “Complete amino acid sequence of a novel integrin &bgr; subunit . . . ”J. Biol. Chem.265 (20) :11502-11507 (1990).
Pytela Robert
Quaranta Vito
Sheppard Dean
Gambel Phillip
Roark Jessica H.
The Regents of the University of California
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