Mount Sinai Hospital Corporation

University of California

The University of North Carolina at Chapel Hill

Ariad Pharmaceuticals, Inc.

Asahi Chemical Industry Co., Ltd.

Anthony J Pawson

Channing J Der

Gerry R Boss

Mark J Zoller

Peter Van Der Geer

Lynne Zydowsky

Kenneth Letwin

Michael Reedijk

John O'Bryan

Jurgen S Scheele

Kazunori Toma

Abhijit Guha

Lily Shiue

Sandra Wiley

Jay Morganstern

Mark Henkemeyer

Gerald Gish

Joan Brugge

Novel receptor tyrosine kinase protein and isoforms thereof which are expressed in migrating axons, and nucleic acid molecules encoding the novel protein isoforms and parts thereof are disclosed. The invention also relates to methods for identifying substances which are capable of binding to the receptor protein and methods for screening for agonists or antagonists of the binding of the protein and substance. Diagnostic and therapeutic methods using the protein and nucleic acid molecules are also described.

Neural receptor tyrosine kinase

A Shc protein which is characterized as follows: (a) containing a C-terminal Src homology 2 (SH2) domain, a central proline-rich region (CH1), and an N-terminal phosphotyrosine binding (PTB) domain; (b) it is predominantly expressed in the adult brain; (c) it binds through its SH2 domain to proteins containing the consensus sequence pTyr-(hydrophobic/Glu)-(hydrophobic/Met/Tyr/Ile)-(Ile/Leu/Met/Phe/Tyr); and (d) it associates through its PTB domain with proteins containing the consensus sequence Asn-Pro-X-pTyr where X is any amino acid; nucleic acids encoding the protein; and uses of the protein. The Shc proteins mediate signaling from tyrosine kinases in the nervous system.

Shc proteins

Peptide inhibitors of a phosphotyrosine-binding domain containing protein

Human syk

A method for assaying a medium for the presence of a substance that affects an SH2-phosphorylated ligand regulatory system. The method employs an SH2-like domain or a subdomain thereof and a phosphorylated ligand. The phosphophorylated ligand is capable of interacting with the SH2-like domain or a subdomain thereof to form an SH2-phosphorylated ligand complex. The SH2-like domain or subdomain and/or the phosphorylated ligand are present in a known concentration. The SH2-like domain or a subdomain thereof and the phosphorylated ligand are incubated with a substance which is suspected of affecting an SH2-phosphorylated ligand regulatory system. The method is carried out under conditions which permit the formation of the SH2-phosphorylated ligand complex. SH2-phosphorylated ligand complex, free SH2-like domain or subdomains thereof, or non-complexed phosphorylated ligand are assayed. The invention also relates to an isolated SH2-phosphorylated ligand complex; a method of using an isolated SH2-like domain or a subdomain thereof to screen for phosphorylated ligands which are active in an SH2-phosphorylated ligand regulatory system; a method of using an isolated SH2-like domain or a subdomain thereof to regulate the interaction of a signalling protein with a related phosphorylated ligand; and a pharmaceutical composition comprising an isolated SH2-like domain or a subdomain thereof for use as an agonist or antagonist of the interaction of a signalling protein with a related phosphorylated ligand.

Method for assaying for a substance that affects an SH2-phosphoraylated

The invention features methods for measuring the total amounts of G protein-bound GDP and GTP in mammalian cells and tissue. The method of the invention is advantageous over conventional methods in that the cells need not be exposed to phosphate-free growth conditions, which can adversely affect the accuracy of the GTP determination. Moreover, the method does not require exposure of the cells to radiolabelled phosphate in the growth medium. Standardized amounts of G protein-bound GDP and GTP are determined relative to non-nuclear cellular protein content or cellular DNA content, allowing comparison of results across different cell types. The method is particularly applicable to the detection of Ras protein bound GTP and GDP. The determination of Ras-bound GTP levels by the method of the invention provides a sensitive and accurate means of evaluating the role of Ras activation in cellular processes, such as cell proliferative disease, hormonal secretion, cellular differentiation, programmed cell death, cell cycle regulation, and protein trafficking. Treatment of abnormal processes can then more accurately targeted to the alteration of G protein activation.

Method of quantitating GTP and GDP bound to a G protein and uses thereof

A method for assaying a medium for the presence of a substance that affects an SH2-phosphorylated ligand regulatory system. The method employs an SH2-like domain or a subdomain thereof and a phosphorylated ligand. The phosphophorylated ligand is capable of interacting with the SH2-like domain or a subdomain thereof to form an SH2-phosphorylated ligand complex. The SH2-like domain or subdomain and/or the phosphorylated ligand are present in a known concentration. The SH2-like domain or a subdomain thereof and the phosphorylated ligand are incubated with a substance which is suspected of affecting an SH2-phosphorylated ligand regulatory system. The method is carried out under conditions which permit the formation of the SH2-phosphorylated ligand complex. SH2-phosphorylated ligand complex, free SH2-like domain or subdomains thereof, or non-complexed phosphorylated ligand are assayed. The invention also relates to an isolated SH2-phosphorylated ligand complex; a method of using an isolated SH2-like domain or a subdomain thereof to screen for phosphorylated ligands which are active in an SH2-phosphorylated ligand regulatory system; a method of using an isolated SH2-like domain or a subdomain thereof to regulate the interaction of a signalling protein with a related phosphorylated ligand; and a pharmaceutical composition comprising an isolated SH2-like domain or a subdomain thereof for use as an agohist or antagonist of the interaction of a signalling protein with a related phosphorylated ligand.

Method for assaying for a substance that affects an SH2 phosphorylated

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Toronto, Canada

Anthony J Pawson