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Covalent capture of kinase substrate...

Blethrow, Justin.

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Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks./
Author:	Blethrow, Justin.
Description:	347 p.
Notes:	Adviser: Kevan M. Shokat.
Contained By:	Dissertation Abstracts International68-11B.
Subject:	Biology, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3289325
ISBN:	9780549333272

Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks.
Blethrow, Justin.

Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks. - 347 p.

Adviser: Kevan M. Shokat.

Thesis (Ph.D.)--University of California, San Francisco, 2007.

Kinase-mediated protein phosphorylation regulates nearly every cellular signaling pathway. Protein kinases function in the integration and modulation of information flow through the regulation of signaling components and act as direct effectors of cellular processes by controlling the behavior of protein machines and cellular structural components. Approximately one third of all cellular proteins are phosphorylated, and so it is thought that many individual kinases likely have numerous (>100) direct targets. A detailed understanding of this architecture will be required in order to accurately model complex cellular behaviors both normal and aberrant, to reliably predict cellular responses to therapeutic intervention in disease states, and to successfully implement cell or tissue based therapeutic strategies. Such an understanding will require a comprehensive elucidation of biologically relevant kinase-substrate interactions. At present, the discovery of such interactions represents a significant challenge.

ISBN: 9780549333272Subjects--Topical Terms:

1018625
Biology, General.

Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks.
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020 $a 9780549333272
035 $a (UMI)AAI3289325
035 $a AAI3289325
040 $a UMI $c UMI
100 1 $a Blethrow, Justin. $3 1264831
245 1 0 $a Covalent capture of kinase substrate phosphopeptides for analysis of cellular signaling networks.
300 $a 347 p.
500 $a Adviser: Kevan M. Shokat.
500 $a Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7314.
502 $a Thesis (Ph.D.)--University of California, San Francisco, 2007.
520 $a Kinase-mediated protein phosphorylation regulates nearly every cellular signaling pathway. Protein kinases function in the integration and modulation of information flow through the regulation of signaling components and act as direct effectors of cellular processes by controlling the behavior of protein machines and cellular structural components. Approximately one third of all cellular proteins are phosphorylated, and so it is thought that many individual kinases likely have numerous (>100) direct targets. A detailed understanding of this architecture will be required in order to accurately model complex cellular behaviors both normal and aberrant, to reliably predict cellular responses to therapeutic intervention in disease states, and to successfully implement cell or tissue based therapeutic strategies. Such an understanding will require a comprehensive elucidation of biologically relevant kinase-substrate interactions. At present, the discovery of such interactions represents a significant challenge.
520 $a In this work we describe a novel method for rapid identification of protein kinase substrates. In this method, a kinase of interest is engineered to accept an ATP analog that allows it to uniquely label its substrates with a bio-orthogonal phosphate analog tag. A highly specific, covalent capture-and-release methodology was developed for rapid purification of tagged peptides derived from labeled substrate proteins. Mass spectrometric analysis of the recovered peptides affords identification of the parent protein species, and often the exact site of phosphorylation. Our experiments show that tagged may be purified from complex mixtures with extremely high specificity. Importantly, we found the sensitivity of the method to be sufficient for the recovery of picomole scale targets from milligrams of cell extract digest. This is a regime suitable for the identification of novel kinase substrates after their specific tagging by as-kinases in cell extracts. Application of this approach to the discovery of Cdk1-Cyclin B substrates in cell extracts yielded identification of over seventy substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been previously characterized as Cdk1-Cyclin B substrates. This approach has the potential to expand our understanding of kinase-substrate connections in signaling networks.
590 $a School code: 0034.
650 4 $a Biology, General. $3 1018625
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0306
690 $a 0307
690 $a 0487
710 2 $a University of California, San Francisco. $b Chemistry and Chemical Biology. $3 1263267
773 0 $t Dissertation Abstracts International $g 68-11B.
790 $a 0034
790 1 0 $a Burlingame, Alma $e committee member
790 1 0 $a Morgan, David O. $e committee member
790 1 0 $a Shokat, Kevan M., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3289325