Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target

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Abstract

The partner of activated epidermal growth factor receptor (EGFR), growth factor receptor bound protein-7 (Grb7), a functionally multidomain adaptor protein, has been demonstrated to be a pivotal regulator for varied physiological and pathological processes by interacting with phospho-tyrosine-related signaling molecules to affect the transmission through a number of signaling pathways. In particular, critical roles of Grb7 in erythroblastic leukemia viral oncogene homolog (ERBB) family-mediated cancer development and malignancy have been intensively evaluated. The overexpression of Grb7 or the coamplification/cooverexpression of Grb7 and members of the ERBB family play essential roles in advanced human cancers and are associated with decreased survival and recurrence of cancers, emphasizing Grb7′s value as a prognostic marker and a therapeutic target. Peptide inhibitors of Grb7 are being tested in preclinical trials for their possible therapeutic effects. Here, we review the molecular, functional, and clinical aspects of Grb7 in ERBB family-mediated cancer development and malignancy with the aim to reveal alternative and effective therapeutic strategies.

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Emerging Roles of Focal Adhesion Kinase in Cancer

Yu-Ling Tai, Lih-Chyang Chen, Tang-Long Shen (2015)

Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. The kinase-dependent and kinase-independent scaffolding functions of FAK modulate the authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancer progression and metastasis. The overexpression and activation of FAK are usually investigated in primary or metastatic cancers and correlated with the poor clinical outcome, highlighting FAK as a potential prognostic marker and anticancer target. Small molecule inhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials. In this review, we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategies for the invention of cancer development and malignancy.

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Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases.

Nolan Priedigkeit, Ryan Hartmaier, Yijing Chen … (2017)

Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies.

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Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette.

Craig Wilson, D Bregman, Jean C. Lee … (2000)

Caveolin-1 was first identified as a phosphoprotein in Rous sarcoma virus (RSV)-transformed chicken embryo fibroblasts. Tyrosine 14 is now thought to be the principal site for recognition by c-Src kinase; however, little is known about this phosphorylation event. Here, we generated a monoclonal antibody (mAb) probe that recognizes only tyrosine 14-phosphorylated caveolin-1. Using this approach, we show that caveolin-1 (Y14) is a specific tyrosine kinase substrate that is constitutively phosphorylated in Src- and Abl-transformed cells and transiently phosphorylated in a regulated fashion during growth factor signaling. We also provide evidence that tyrosine-phosphorylated caveolin-1 is localized at the major sites of tyrosine-kinase signaling, i.e. focal adhesions. By analogy with other signaling events, we hypothesized that caveolin-1 could serve as a docking site for pTyr-binding molecules. In support of this hypothesis, we show that phosphorylation of caveolin-1 on tyrosine 14 confers binding to Grb7 (an SH2-domain containing protein) both in vitro and in vivo. Furthermore, we demonstrate that binding of Grb7 to tyrosine 14-phosphorylated caveolin-1 functionally augments anchorage-independent growth and epidermal growth factor (EGF)-stimulated cell migration. We discuss the possible implications of our findings in the context of signal transduction.

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Author and article information

Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 10 May 2019

Publication date Collection: May 2019

Volume: 8

Issue: 5

Electronic Location Identifier: 435

Affiliations

[1 ]Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan; areteka@ 123456gmail.com (P.-Y.C.); d98633002@ 123456ntu.edu.tw (Y.-L.T.)

[2 ]Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

[3 ]Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan

Author notes

[* ]Correspondence: shentl@ 123456ntu.edu.tw ; Tel.: +886-2-3366-4998

[†]

These authors contributed equally to this work.

Author information

Pei-Yu Chu https://orcid.org/0000-0003-3874-6986

Yu-Ling Tai https://orcid.org/0000-0001-8609-1158

Article

Publisher ID: cells-08-00435

DOI: 10.3390/cells8050435

PMC ID: 6562560

PubMed ID: 31083325

SO-VID: 070baacd-3115-4db4-94b2-349c05b8e483

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target

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Neuronal Signaling

Most cited references 76

Emerging Roles of Focal Adhesion Kinase in Cancer

Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases.

Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette.

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