Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity

The Journal of Cell Biology ◽

10.1083/jcb.201204106 ◽

2013 ◽

Vol 200 (4) ◽

pp. 493-504 ◽

Cited By ~ 37

Author(s):

Zamal Ahmed ◽

Chi-Chuan Lin ◽

Kin M. Suen ◽

Fernando A. Melo ◽

James A Levitt ◽

...

Keyword(s):

Growth Factor ◽

Phosphatase Activity ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Adaptor Protein ◽

Sh2 Domain ◽

Receptor Kinase ◽

Downstream Signaling ◽

State Growth ◽

Kinase Phosphorylation

Constitutive receptor tyrosine kinase phosphorylation requires regulation of kinase and phosphatase activity to prevent aberrant signal transduction. A dynamic mechanism is described here in which the adaptor protein, growth factor receptor–bound protein 2 (Grb2), controls fibroblast growth factor receptor 2 (FGFR2) signaling by regulating receptor kinase and SH2 domain–containing protein tyrosine phosphatase 2 (Shp2) phosphatase activity in the absence of extracellular stimulation. FGFR2 cycles between its kinase-active, partially phosphorylated, nonsignaling state and its Shp2-dephosphorylated state. Concurrently, Shp2 cycles between its FGFR2-phosphorylated and dephosphorylated forms. Both reciprocal activities of FGFR2 and Shp2 were inhibited by binding of Grb2 to the receptor. Phosphorylation of Grb2 by FGFR2 abrogated its binding to the receptor, resulting in up-regulation of both FGFR2’s kinase and Shp2’s phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2–Grb2 complex. This cycling of enzymatic activity results in a homeostatic, signaling-incompetent state. Growth factor binding perturbs this background cycling, promoting increased FGFR2 phosphorylation and kinase activity, Grb2 dissociation, and downstream signaling. Grb2 therefore exerts constitutive control over the mutually dependent activities of FGFR2 and Shp2.

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Characterization of AZD8931, a potent reversible small molecule inhibitor against epidermal growth factor receptor (EGFR), erythroblastic leukemia viral oncogene homolog 2 (HER2) and 3 (HER3) with a unique and balanced pharmacological profile

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11072 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11072-11072

Author(s):

G. Speake ◽

T. Klinowska ◽

M. Hickinson ◽

G. Marshall ◽

P. Smith ◽

...

Keyword(s):

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Receptor Activation ◽

Erbb Receptors ◽

Pharmacological Profile ◽

Her Family ◽

Pharmacological Inhibition ◽

Downstream Signaling ◽

Additional Clinical Benefit

11072 Background: Successful combined pharmacological inhibition of EGFR, HER2, and HER3 signaling is currently under investigation in the clinic. HERs (erbB receptors including EGFR, erbB2, erbB3, erbB4) undergo various types of alteration and in many cancers HER ligands are produced either by the tumor cells themselves or surrounding stromal cells. These mechanisms of receptor activation all lead to constitutive proliferative and/or survival signaling driven by homo- and/or heterodimerization of the HER family. Characterization of a novel tyrosine kinase inhibitor with a potent and balanced profile against EGFR, HER2 (erbB2), and HER3 (erbB3) has been carried out. Methods: A range of assays has been developed to assess the detailed pharmacology of AZD8931 and understand how the profile of AZD8931 compares with other HER family inhibitors, such as gefitinib and lapatinib. These assays have provided unique insights into the pharmacology of these drugs that result from the varying levels of HER and their associated ligands. Results: Across a number of cell systems, AZD8931 has been shown to be a potent inhibitor of tumor cell growth. This effect is through the ability of AZD8931 to inhibit potently the phosphorylation of EGFR (0.004 μM; 95% CIR: 1.377), HER2 (0.003 μM; 95% CIR: 1.817) and HER3 (0.004 μM; 95% CIR: 1.890) in a balanced manner. Furthermore, when compared to control AZD8931 has significant and dramatic effects on the downstream signaling pathways (pAKT [p=0.002] & pMAK [NS]), apoptotic (M30 [p=0.004]), and proliferative (Ki67 [p<0.0005]) endpoints. The novel agent AZD8931 displays a distinct pharmacological profile compared to both gefitinib and lapatinib. Conclusions: Based on our data as well as published literature, the combined pharmacological inhibition of EGFR, HER2, and HER3 signaling has not yet been tested in the clinic. AZD8931 offers an agent to test the hypothesis that combined inhibition of HER signaling could provide additional clinical benefit in cancer, particularly in the majority of solid tumors that do not overexpress HER2. [Table: see text]

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Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Endocrine Related Cancer ◽

10.1530/erc-16-0218 ◽

2016 ◽

Vol 23 (11) ◽

pp. R527-R550 ◽

Cited By ~ 10

Author(s):

Aleksandra M Ochnik ◽

Robert C Baxter

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Cancer Therapy ◽

Therapeutic Target ◽

Growth Factor Receptor ◽

Insulin Like Growth Factor ◽

Breast Cancers ◽

Downstream Signaling ◽

Intrinsic Complexity ◽

Igf1r Signaling

Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity  and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers.

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SH3KBP1 Promotes Glioblastoma Tumorigenesis by Activating EGFR Signaling

Frontiers in Oncology ◽

10.3389/fonc.2020.583984 ◽

2021 ◽

Vol 10 ◽

Author(s):

Hai Song ◽

Yanpei Wang ◽

Chaojia Shi ◽

Jianxiang Lu ◽

Tian Yuan ◽

...

Keyword(s):

Growth Factor Receptor ◽

Adaptor Protein ◽

Egfr Signaling ◽

Potential Therapeutic Target ◽

Downstream Signaling ◽

Protein Levels ◽

Egfr Activation ◽

Epidermal Growth

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Overexpression or activation of epidermal growth factor receptor (EGFR) occurs commonly in multiple human cancers and promotes tumorigenesis. However, the underlying molecular mechanism of EGFR aberrant activation and the downstream signaling pathways remains largely unknown. In this study, we report that both SH3-domain kinase binding protein 1 (SH3KBP1) mRNA and protein levels are highly expressed in GBM and its high expression is associated with worse survival of glioma patients. In addition, we provide evidence that SH3KBP1 is prominently expressed in GBM stem cells (GSCs) and have potential to serve as a novel GSCs marker. Moreover, silencing SH3KBP1 dramatically impairs GBM cell proliferation, migration and GSCs self-renewal ability in vitro and xenograft tumors growth in vivo. Most importantly, we found that SH3KBP1 directly interacts with EGFR and may act as an adaptor protein to transduce EGFR signaling. Together, our work uncovers SH3KBP1 as a novel regulator of oncogenic EGFR signaling and also as a potential therapeutic target for GBM patients with EGFR activation.

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Detection of FGFR3 by Immunohistochemistry in Multiple Myeloma Is Highly Predictive of t(4;14) by FISH and Is Associated with CD56 (NCAM1) Expression.

Blood ◽

10.1182/blood.v108.11.5073.5073 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5073-5073

Author(s):

Nizar J. Bahlis ◽

Birgitte Roland ◽

Toni Maggliocco ◽

Ivona Auer ◽

Douglas A. Stewart ◽

...

Keyword(s):

Multiple Myeloma ◽

Cyclin D1 ◽

Cell Adhesion Molecule ◽

Growth Factor Receptor ◽

Direct Interaction ◽

Aberrant Expression ◽

Downstream Signaling ◽

Neural Cell Adhesion ◽

Cd56 Expression ◽

Adhesive Interactions

Abstract Recent studies have demonstrated that neural cell adhesion molecule CD56 (NCAM1) is involved in multiple adhesive interactions with several different classes of ligands on the cell surface and in the extracellular matrix. One of these ligands is fibroblast growth factor receptor (FGFR) family. While a direct interaction between CD56 (NCAM1) and FGFR3 is yet to be reported we have speculated that such interaction might exist in myeloma cells with aberrant FGFR3 expression. In order to test this hypothesis we have retrospectively examined the presence of t(4;14) in 127 multiple myeloma samples and its correlation with the presence of deletion 13 by FISH; FGFR3 and cyclin D1 expression by immunohistochemistry and CD56 expression as determined by flow cytometry. FISH detected t(4;14) in 32 (25.1%) of 127 MM patient specimens. 71.4% of t(4;14) positive samples were found to have deletion of chromosome 13, in contrast to only 34% in t(4;14) negative samples. Aberrant expression of FGFR3 was detected by immunohistochemistry in 14/21 or 66.7% of t(4;14) positive samples. No expression of FGFR3 was detected in 10 t(4;14) negative samples. As expected low Cyclin D1 expression by IHC was detected in t(4;14) positive samples (5/21 or 23.8%). More importantly all samples positive for FGFR3 by IHC were CD56 positive (14/14 or 100%) and in 21/22 (95.5%) of t(4;14) positive in contrast to 62% in t(4;14) samples. Further work is currently being conducted in order to examine the downstream signaling pathways that might be activated as a result of such possible interaction.

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Muc4–ErbB2 Complex Formation and Signaling in Polarized CACO-2 Epithelial Cells Indicate That Muc4 Acts as an Unorthodox Ligand for ErbB2

Molecular Biology of the Cell ◽

10.1091/mbc.e05-09-0895 ◽

2006 ◽

Vol 17 (7) ◽

pp. 2931-2941 ◽

Cited By ~ 38

Author(s):

Victoria P. Ramsauer ◽

Vanessa Pino ◽

Amjad Farooq ◽

Coralie A. Carothers Carraway ◽

Pedro J.I. Salas ◽

...

Keyword(s):

Epithelial Cells ◽

Complex Formation ◽

Receptor Tyrosine Kinase ◽

Mammalian Cells ◽

Apical Cell ◽

Adaptor Protein ◽

Signaling Cascades ◽

Erbb Receptors ◽

Downstream Signaling ◽

Muc4 Expression

Muc4 serves as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The time to complex formation and the stoichiometry of the complex were determined to be <15 min and 1:1 by analyses of Muc4 and ErbB2 coexpressed in insect cells and A375 tumor cells. In polarized CACO-2 cells, Muc4 expression causes relocalization of ErbB2, but not its heterodimerization partner ErbB3, to the apical cell surface, effectively segregating the two receptors. The apically located ErbB2 is phosphorylated on tyrosines 1139 and 1248. The phosphorylated ErbB2 in CACO-2 cells recruits the cytoplasmic adaptor protein Grb2, consistent with previous studies showing phosphotyrosine 1139 to be a Grb2 binding site. To address the issue of downstream signaling from apical ErbB2, we analyzed the three MAPK pathways of mammalian cells, Erk, p38, and JNK. Consistent with the more differentiated phenotype of the CACO-2 cells, p38 phosphorylation was robustly increased by Muc4 expression, with a consequent activation of Akt. In contrast, Erk and JNK phosphorylation was not changed. The ability of Muc4 to segregate ErbB2 and other ErbB receptors and to alter downstream signaling cascades in polarized epithelial cells suggests that it has a role in regulating ErbB2 in differentiated epithelia.

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