Memo is a cofilin-interacting protein that influences PLCγ1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration

Meira, Maria; Masson, Régis; Štagljar, Igor; Lienhard, Susanne; Maurer, Fabienne; Boulay, Anne; Hynes, Nancy E.

doi:10.1242/jcs.032094

Cited by 33 publications

(65 citation statements)

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“…PLCg1 and Memo were shown to interact with pTyr1996 and pTyr1222, respectively, and cells with KD of either protein were impaired in HRG-induced directional migration (Meira et al, 2009). Using a KD approach, we show here that Copine-III is also required for HRGinduced T47D cell migration.…”

Section: Discussionmentioning

confidence: 76%

“…It is tempting to speculate that in cells with low Copine-III, ErbB2 loses its ability to couple to proteins and pathways involved in motility. Considering these and other proteins that interact with ErbB2, we propose the following model: in response to ligand activation, ErbB2 binds and activates PLCg1 (Meira et al, 2009), which causes an increase in diacylglycerol levels and initiates Ca 2 þ influx from the endoplasmic reticulum and through store-operated channels into the cytoplasm (Patterson et al, 2005;Kheifets and Mochly-Rosen, 2007). Interestingly, specific residues that have been mapped in the C2D of PKCa as being essential for RACK1 binding (McCahill et al, 2002) are conserved in Copine-III C2D-B.…”

Section: Discussionmentioning

confidence: 99%

“…ErbB2 was found in IPs of Copine-III from lysates of T47D and SKBr3 cells (Figures 5c and e). In control cells an association of ErbB2 and Copine-III was detected, reflecting autocrine receptor activity in T47D cells (Meira et al, 2009) and ErbB2 overexpression in SKBr3 cells (Lane et al, 2000). In Copine-III IPs from lysates of HRG-treated cells, there was an increase in complexed, active pTyrcontaining ErbB2 (Figure 5c and e).…”

Section: Tr Erbb2mentioning

confidence: 90%

“…The role of pTyr residues has also been examined in migration assays. In T47D breast tumor cells, Tyr1196 and Tyr1222 each have been linked to ErbB2-mediated cell migration through PLCg and Memo, respectively (Marone et al, 2004;Meira et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Immunofluorescence microscopy Preparation of cells was performed as previously described (Meira et al, 2009). Images were recorded with an Axioskop Zeiss microscope (Jena, Thu¨ringen, Germany) coupled to a Sony 3 CDD camera.…”

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Copine-III interacts with ErbB2 and promotes tumor cell migration

et al. 2009

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ErbB2 amplification and overexpression in breast cancer correlates with aggressive disease and poor prognosis. To find novel ErbB2-interacting proteins, we used stable isotope labeling of amino acids in cell culture followed by peptide affinity pull-downs and identified specific binders using relative quantification by mass spectrometry. Copine-III, a member of a Ca 2 þ -dependent phospholipid-binding protein family, was identified as binding to phosphorylated Tyr1248 of ErbB2. In breast cancer cells, Copine-III requires Ca 2 þ for binding to the plasma membrane, where it interacts with ErbB2 upon receptor stimulation, an interaction that is dependent on receptor activity. Copine-III also binds receptor of activated C kinase 1 and colocalizes with phosphorylated focal adhesion kinase at the leading edge of migrating cells. Importantly, knockdown of Copine-III in T47D breast cancer cells causes a decrease in Src kinase activation and ErbB2-dependent wound healing. Our data suggest that Copine-III is a novel player in the regulation of ErbB2-dependent cancer cell motility. In primary breast tumors, high CPNE3 RNA levels significantly correlate with ERBB2 amplification. Moreover, in an in situ tissue microarray analysis, we detected differential protein expression of Copine-III in normal versus breast, prostate and ovarian tumors, suggesting a more general role for Copine-III in carcinogenesis.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Tr Erbb2mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Copine-III interacts with ErbB2 and promotes tumor cell migration

et al. 2009

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Identification of Phenazine‐Based MEMO1 Small‐Molecule Inhibitors: Virtual Screening, Fluorescence Polarization Validation, and Inhibition of Breast Cancer Migration

et al. 2021

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Phosphorylation‐dependent protein–protein interactions play a significant role in biological signaling pathways; therefore, small molecules that are capable of influencing these interactions can be valuable research tools and have potential as pharmaceutical agents. MEMO1 (mediator of ErbB2‐cell driven motility) is a phosphotyrosine‐binding protein that interacts with a variety of protein partners and has been found to be upregulated in breast cancer patients. Herein, we report the first small‐molecule inhibitors of MEMO1 interactions identified through a virtual screening platform and validated in a competitive fluorescence polarization assay. Initial structure–activity relationships have been investigated for these phenazine‐core inhibitors and the binding sites have been postulated using molecular dynamics simulations. The most potent biochemical inhibitor is capable of disrupting the large protein interface with a KI of 2.7 μm. In addition, the most promising phenazine core compounds slow the migration of breast cancer cell lines in a scratch assay.

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The cofilin activity cycle in lamellipodia and invadopodia

Oser

Condeelis

2009

J of Cellular Biochemistry

163

168

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The actin severing protein cofilin is essential for directed cell migration and chemotaxis, in many cell types and is also important for tumor cell invasion during metastasis. Through its severing activity, cofilin increases the number of free barbed ends to initiate actin polymerization for actin-based protrusion in two distinct subcellular compartments in invasive tumor cells: lamellipodia and invadopodia. Cofilin severing activity is tightly regulated and multiple mechanisms are utilized to regulate cofilin activity. In this prospect, we have grouped the primary on/off regulation into two broad categories, both of which are important for inhibiting cofilin from binding to F-actin or G-actin: (1) Blocking cofilin activity by the binding of cofilin to either PI(4,5)P2 at lamellipodia, or cortactin at invadopodia. (2) Blocking cofilin's ability to bind to actin via serine phosphorylation. Although the literature suggests that these cofilin regulatory mechanisms may be cell-type dependent, we propose the existence of a common cofilin activity cycle in which both operate. In this common cycle, the mechanism used to initiate cofilin activity is determined by the starting point in the cycle in a given subcellular compartment.

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Memo is a cofilin-interacting protein that influences PLCγ1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration

Abstract: Heregulin (HRG) activatesSupplementary material available online at

Cited by 33 publications

References 50 publications

Copine-III interacts with ErbB2 and promotes tumor cell migration

Copine-III interacts with ErbB2 and promotes tumor cell migration

Identification of Phenazine‐Based MEMO1 Small‐Molecule Inhibitors: Virtual Screening, Fluorescence Polarization Validation, and Inhibition of Breast Cancer Migration

The cofilin activity cycle in lamellipodia and invadopodia

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