GRB7

Official Full Name

growth factor receptor bound protein 7

Organism

Homo sapiens

GeneID

2886

Background

The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with epidermal growth factor receptor (EGFR) and ephrin receptors. The protein plays a role in the integrin signaling pathway and cell migration by binding with focal adhesion kinase (FAK). Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

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Detailed Information

Tumor development and progression into a metastatic and malignant state involve deregulation of signaling pathways governing cell proliferation, survival, and migration. Therefore, key signaling proteins that are aberrantly overexpressed or act at critical junctions in cancer are of interest for their potential as therapeutic targets. Growth factor receptor-bound protein 7 (Grb7) is an intracellular signaling protein with crucial roles in cancer cell proliferation and migration that has been found to be overexpressed in cancers of the breast, ovaries, pancreas and esophagus.

The multi-adaptor protein Grb7 operates through distinct signaling pathways to induce cell proliferation and migration in the progression of various cancer types including the breast cancer subclasses HER2+ and triple negative breast cancer (TNBC). In HER2+ cell lines, Grb7 is co-overexpressed with HER2, the well-known predictor for a poor prognosis in breast cancer patients, with Grb7 facilitating aberrant proliferative signaling. The inhibition or removal of Grb7 has been shown to reduce breast cancer cell viability and increase the activity of anti-HER2 cancer therapeutics. Grb7 has also been shown to play an important role in the migratory potential of cancer cells. In both HER2+ and TNBC cell lines, inhibition of Grb7 impairs cell migration and invasion as well as colony growth. In addition, in a mouse model of pancreatic cancer, Grb7 inhibition reduced cancer cell metastasis. Clinical investigations have shown that Grb7 overexpression is significantly associated with a higher clinical stage and larger tumor size for patients with breast cancer, and is a significant predictor for reduced cancer-free periods. Therefore, Grb7, which acts at the nexus of both growth and migratory signaling pathways, has been identified as a therapeutic target for the treatment of several cancer types including HER2+ and TNBC.

Grb7 is a 532 amino acid modular protein that consists of an N-terminal proline-rich region, a central GM (for Grb and Mig) domain and a C-terminal SH2 domain. The central GM region encompasses the Ras-associating (RA) domain, pleckstrin homology (PH) domain, and the between PH and SH2 (BPS) domain. It is through the C-terminal SH2 domain that Grb7 interacts with its upstream receptor tyrosine kinases and other signaling molecules including EGFR, HER2, HER3, and FAK, allowing Grb7 to propagate downstream signaling.

Therefore, it is the SH2 domain that has been the target for inhibitor development to date. A non-phosphorylated thioether-linked cyclic peptide 1, named G7-18NATE (cyclo-(CH2COWFEGYDNTFPC)-amide), was identified via phage display to inhibit interactions between Grb7 and HER3 in breast cancer cell extracts. When peptide 1 was attached to the penetration cell permeability sequence (1P), it was shown to inhibit migration and proliferation in breast and pancreatic cancer cell lines, as well as reduce tumor metastasis in a pancreatic mouse model derived from Grb7 overexpressing cells. Moreover, peptide 1P and other cell permeable forms of peptide 1 were identified to have synergistic effects with the currently available therapeutics Doxorubicin and Trastuzumab in inhibiting proliferation and migration in breast cancer cell lines. Therefore, peptide 1 is a successful peptide for inhibiting Grb7 in breast cancer assays, and a promising starting point for therapeutics targeting breast cancer.

Recently, researchers showed the synthesis and analysis of triazole- (peptide 3) and lactam-linked (peptides 4 and 5) bicyclic Grb7-SH2 inhibitors that are specific for Grb7 and achieve binding affinities up to KD = 270 nM. Cell-permeable versions of the optimized peptide inhibitors were shown to block Grb7 interactions with HER2, FAK and SHC upstream binding partners in a HER2+ breast cancer cell line. Together this work demonstrates the rational structure-based progression towards the most potent Grb7-SH2 domain peptides developed to date. These peptides represent valuable tools for understanding Grb7 function and are a significant advancement in the development of Grb7-targeted anti-cancer agents.

References:

Watson G M, et al. Discovery, Development and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target. Journal of Medicinal Chemistry, 2017:acs.jmedchem.7b01320.
Watson G M, et al. Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target. Journal of Medicinal Chemistry, 2015, 58(19):7707-18.

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