New York University

Benjamin L Margolis

Joseph Schlessinger

Edward Y Skolnik

Harald App

Vijay Yajnik

The present invention relates to compositions and methods for the prevention, prognostic evaluation, and treatment of oncogenic disorders, especially breast cancer, wherein a protein tyrosine kinase capable of complexing with a member of the SH2- and/or SH3-containing family of adaptor proteins is involved. In a preferred embodiment of the invention, the protein tyrosine kinase is the receptor protein tyrosine kinase HER2, and the adaptor protein is GRB, so that the protein tyrosine kinase/adaptor protein complex is a HER2/GRB-7 complex.

Prognostic evaluation of cancer

The present invention relates to a novel method, based on direct expression cloning, for identifying target proteins capable of binding to and/or serving as substrates for receptor or cytoplasmic tyrosine kinases. The present invention also relates to novel proteins identified using this method, and to methods for identifying compounds that disrupt the interaction of such novel proteins with the receptor or cytoplasmic tyrosine kinases.

Expression-cloning method for identifying target proteins for eukaryotic tyrosine kinases and novel target proteins

Methods that detect compounds that disrupt receptor tyrosine

The present invention relates to compositions and methods for the prevention, prognostic evaluation, and treatment of oncogenic disorders, especially breast cancer, wherein a protein tyrosine kinase capable of complexing with a member of the SH2-and/or SH3-containing family of adaptor proteins is involved. In a preferred embodiment of the invention, the protein tyrosine kinase is the receptor protein tyrosine kinase HER2 or SHC polypeptide, and the adaptor protein is GRB-7, so that the protein tyrosine kinase/adaptor protein complex is a HER2/GRB-7 complex or a SHC/GRB-7 complex.

Methods for disrupting GRB-7 complexes

Expression-cloning method for identifying target proteins for eukaryotic

A novel expression cloning method is provided for the detection, identification and purification of target proteins capable of binding at least to a tryosine-phosphorylated domain of a eukaryotic tyrosine kinase using novel peptide probes comprising an amino acid sequence substantially corresponding to a portion of a tyrosine-phosphorylated domain of a tyrosine kinase. The probe has at least one phosphorlated tyrosine residue and may be detectably labeled. Also disclosed is a method for preparing the probe, a method for mapping to a chormosome a gene encoding a protein capable of binding to tyrosine-phosphorylated domains of tyrosine kinases, and a method for purifiying such a protein with the probe. Non-limiting examples of novel proteins discovered using the above cloning method include GRB-1, GRB-2, GRB-3, GRB-4 and GRB-7, as well as nucleic acid encoding these proteins, and methods for detecting these proteins are also provided.

Methods for detecting tyrosine kinase-binding target proteins and

The present invention concerns methods for diagnosis and treatment of diseases or disorders characterized by abnormal cellular signal transduction involving a newly identified region, herein termed the 'APB domain.' APB domain binding between proteins is believed to play an important role in signal transduction pathways and, thereby, influence cellular events. Thus, APB mediated activity plays a role in signal transduction pathways and agents modulating APB mediated activity can be used to treat diseases or disorders involving proteins containing APB domains.

Methods for treatment or diagnosis of diseases or disorders associated

A novel expression cloning method is provided for the detection, identification and purification of target proteins capable of binding at least to a tryosine-phosphorylated domain of a eukaryotic tyrosine kinase using novel peptide probes comprising an amino acid sequence substantially corresponding to a portion of a tyrosine-phosphorylated domain of a tyrosine kinase. The probe has at least one phosphorlated tyrosine residue and may be detectably labeled. Also disclosed is a method for preparing the probe, a method for mapping to a chormosome a gene encoding a protein capable of binding to tyrosine-phosphorylated domains of tyrosine kinases, and a method for purifiying such a protein with the probe. Non-limiting examples of novel proteins/discovered using the above cloning method include GRB-1, GRB-2, GRB-3, GRB-4 and GRB-7, as well as nucleic acid encoding these proteins, and methods for detecting these proteins are also provided.

Target proteins for eukaryotic tyrosine kinases

Recombinant DNA encoding a eukaryotic tyrosine kinase target protein

A novel expression cloning method is provided for the detection, identification and purification of target proteins capable of binding at least to a tryosine-phosphorylated domain of a eukaryotic tyrosine kinase using novel peptide probes comprising an amino acid sequence substantially corresponding to a portion of a tyrosine-phosphorylated domain of a tyrosine kinase. The probe has at least one phosphorlated tyrosine residue and may be detectably labeled. Also disclosed is a method for preparing the probes a method for mapping to a chormosome a gene encoding a protein capable of binding to tyrosine-phosphorylated domains of tyrosine kinases, and a method for purifiying such a protein with the probe. Non-limiting examples of novel proteins discovered using the above cloning method include GRB-1, GRB-2, GRB-3, GRB-4 and GRB-7, as well as nucleic acid encoding these proteins, and methods for detecting these proteins are also provided.

Growing community of inventors

New York, NY, United States of America

Benjamin L Margolis