The adaptor Grb7 is a novel calmodulin-binding protein: functional implications of the interaction of calmodulin with Grb7

Li, Hongbing; Sánchez-Torres, Juan; Carpio, Alan F del; Nogales, Aitor; Molina-Ortíz, Patricia; Moreno, María; Török, Katalin; Villalobo, Antonio

doi:10.1038/sj.onc.1208591

Cited by 29 publications

(59 citation statements)

References 53 publications

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“…phoinositide-binding domain that is responsible for plasma membrane localization and is also accessible for phosphorylation by FAK (3,4). Structural prediction and biochemical validation both support the direct interaction of the RA domain with Ras-GTPases, similar to the canonical ubiquitin-like folded Ras-binding domain of c-Raf and RalGDS (5).…”

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confidence: 85%

EGF-induced Grb7 Recruits and Promotes Ras Activity Essential for the Tumorigenicity of Sk-Br3 Breast Cancer Cells

Chu

Ding

et al. 2010

Journal of Biological Chemistry

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Co-amplification and co-overexpression of ErbB2 and Grb7 are frequently found in various cancers, including breast cancer. Biochemical and functional correlations of the two molecules have identified Grb7 to be a pivotal mediator downstream of ErbB2-mediated oncogenesis. However, it remains largely unknown how Grb7 is involve in the ErbB2-mediated tumorigenesis. In this study, we show that Grb7-mediated cell proliferation and growth are essential for the tumorigenesis that occurs in ErbB2-Grb7-overexpressing breast cancer cells. Intrinsically, EGF-induced de novo Grb7 tyrosine phosphorylation/activation recruits and activates Ras-GTPases and subsequently promotes the phosphorylation of ERK1/2, thereby stimulating tumor growth. Furthermore, we also found the anti-tumor effect could be synergized by co-treatment with Herceptin plus Grb7 knockdown in Sk-Br3 breast cancer cells. Our findings illustrate an underlying mechanism by which Grb7 promotes tumorigenesis through the formation of a novel EGFR-Grb7-Ras signaling complex, thereby highlighting the potential strategy of targeting Grb7 as an anti-breast cancer therapy.Growth factor receptor-bound protein-7 (Grb7) 2 is the prototype of an emerging adaptor protein family that includes Grb10 and Grb14 and contains an N-terminal proline-rich region followed by a putative RA (Ras-associating) domain, a central PH (pleckstrin homology) domain, a BPS (Between the PH and SH2 domains), motif and a C-terminal SH2 domain (1, 2). Most of these domains are known to interact with a variegated spectrum of receptors and/or regulators, through which Grb7 is capable of activating versatile signal transduction pathways to modulate various cellular functions (1, 2). For instance, the SH2 domain of Grb7 is capable of binding to the phosphotyrosine sites of receptor tyrosine kinases such as ErbB family receptors, PDGF receptor, Tek/Tie2, c-Kit, and EphB1, as well as cytoplasmic proteins such as SHPTP2, Shc, and FAK (focal adhesion kinase) (2). The PH domain is the calmodulin-or phosphoinositide-binding domain that is responsible for plasma membrane localization and is also accessible for phosphorylation by FAK (3, 4). Structural prediction and biochemical validation both support the direct interaction of the RA domain with Ras-GTPases, similar to the canonical ubiquitin-like folded Ras-binding domain of c-Raf and RalGDS (5). Using yeast two-hybrid screening, Tankyrase 2, an ankyrin repeat-containing poly(ADP-ribose) polymerase, was identified to interact with the N-terminal prolinerich region of Grb14 (6). However, the downstream signaling targets of the identified interactions and their corresponding functional consequences remain largely unknown.Originally identified as an activated EGF receptor-binding partner, Grb7 has often been found to be co-amplified with ErbB2 in several cancers because both genes are located in the chromosome 17q12 (7). In fact, Grb7 is concurrently overexpressed with ErbB2 in about 30% of human breast cancers, and in these cases, the patients present a poor ...

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confidence: 85%

EGF-induced Grb7 Recruits and Promotes Ras Activity Essential for the Tumorigenicity of Sk-Br3 Breast Cancer Cells

Chu

Ding

et al. 2010

Journal of Biological Chemistry

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“…Moreover, GRB7 is implicated in cell invasion and metastatic progression of esophageal carcinoma (19,49). Recently, GRB7 has been shown to interact with calmodulin, which may contribute to the high motility observed in many cancer cells, their metastatic spread, and the neovascularization required for tumor progression (50). MLN64 is expressed preferentially in malignant tissues, specifically breast tumors and breast cancer cell lines, but not in normal cells (24).…”

Section: Discussionmentioning

confidence: 99%

Expression of HER2 and the Coamplified Genes GRB7 and MLN64 in Human Breast Cancer: Quantitative Real-time Reverse Transcription-PCR as a Diagnostic Alternative to Immunohistochemistry and Fluorescence In situ Hybridization

Vinatzer

Dampier

Streubel

et al. 2005

Clinical Cancer Research

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Purpose: Accurate testing of HER2 is centrally important for breast cancer therapy and prognosis. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are current standard testing methods. As a potential alternative for assessment of HER2, we explored quantitative real-time reverse transcription-PCR (RT-PCR), a fast and inexpensive method yielding quantitative results insensitive to interobserver variability and amenable to standardized scoring. Experimental Design: We assessed HER2 status at the DNA, mRNA, and protein levels with FISH, quantitative RT-PCR, and IHC in 136 tumor samples from 85 breast cancer patients. Expression of GRB7, MLN64, and p21, genes coregulated with HER2, was also quantified with quantitative RT-PCR and correlated with the overall survival (OS) and disease-free survival (DFS) individually and in combination with HER2. Results: Twenty-nine percent and 19% of the patients scored HER2 positive with IHC and quantitative RT-PCR, respectively. In 18 of 19 cases, HER2 statuses in tumors and lymph node metastases were identical. HER2 status significantly correlated with DFS when determined by IHC (P < 0.01), quantitative RT-PCR (P < 0.003), but not with FISH (P = 0.09). The combination of HER2 with MLN64, but not with GRB7 or p21, enhanced the prognostic power for the DFS (P < 0.00005) and OS (P < 0.0008).Conclusions: Quantitative RT-PCR seems to be clinically as useful in the assessment of HER2 status as IHC and FISH, yielding comparable correlations of HER2 status with the OS and DFS. Thus, quantitative RT-PCR analysis of HER2 or HER2 plus MLN64 is a promising complement or alternative to current methods for HER2 testing, particularly in laboratories lacking FISH or IHC technology.

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“…Interaction between GRB7 and multiple cell surface receptors is known to mediate signal transduction to diverse downstream signaling pathways (Shen & Guan 2004). Several studies have demonstrated that GRB7 plays a key role in cell migration through its association with focal adhesion kinase, phosphoinositides, ephrin receptor EphB1, and calmodulin (Han et al 2000, 2002, Shen et al 2002, Li et al 2005, thus implying a likely role in tumor progression. For example, GRB7 expression has been associated with an invasive phenotype and metastatic progression of tumor cells in esophageal carcinoma (Tanaka et al 1997(Tanaka et al , 2000.…”

Section: Candidate Target Genes At the 17q12-q21 Ampliconmentioning

confidence: 99%

Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer

Kauraniemi¹,

Kallioniemi²

2006

Endocr Relat Cancer

117

104

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During the past decade the role of the ERBB2 (neu/HER2) oncogene as an important predictor of patient outcome and response to various therapies in breast cancer has been clearly established. This association of ERBB2 aberrations with more aggressive disease and poor clinical outcome, together with the high prevalence of such alterations in breast cancer, has also made ERBB2 an attractive target for therapy. A specific antibody-based therapy, Herceptin, directed against the extracellular domain of the ERBB2 receptor tyrosine kinase, was recently developed and several clinical trials have shown the therapeutic efficacy of this drug against ERBB2-positive breast cancer. However, a relatively large fraction of patients does not benefit from Herceptin treatment, indicating that other factors beyond ERBB2 itself must influence therapy response in ERBB2-positive tumors. It is well known that amplification of the 17q12-q21 region is the most common mechanism for ERBB2 activation in breast cancer and that it leads to simultaneous activation of several other genes. These co-amplified and co-activated genes may have an impact on disease progression and the clinical behavior of ERBB2-positive tumors and thus represent important targets of research. In this paper we discuss the current knowledge on the structure of the ERBB2 amplicon, the genes involved, and their possible contribution to breast cancer pathogenesis.

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The adaptor Grb7 is a novel calmodulin-binding protein: functional implications of the interaction of calmodulin with Grb7

Cited by 29 publications

References 53 publications

EGF-induced Grb7 Recruits and Promotes Ras Activity Essential for the Tumorigenicity of Sk-Br3 Breast Cancer Cells

EGF-induced Grb7 Recruits and Promotes Ras Activity Essential for the Tumorigenicity of Sk-Br3 Breast Cancer Cells

Expression of HER2 and the Coamplified Genes GRB7 and MLN64 in Human Breast Cancer: Quantitative Real-time Reverse Transcription-PCR as a Diagnostic Alternative to Immunohistochemistry and Fluorescence In situ Hybridization

Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer

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