β-integrin controls IGF-1R internalisation and intracellular signalling.

Cell adhesion-dependent phosphorylation of Insulin-like Growth Factor 1 Receptor (IGF-1R) on its C-terminal tail (CT) at Tyr promotes receptor internalisation and Golgi accumulation. We previously proposed that this phosphorylation is associated with cell migration and cancer aggressiveness, distinguishing IGF-1R activity from that of Insulin Receptor, which lacks these tyrosines. Here, we further investigated how adhesion signalling influences IGF-1R location and activity in migratory cancer cells and R- fibroblasts.

PDLIM2 is highly expressed in Breast Cancer tumour-associated macrophages and is required for M2 macrophage polarization.

The PDZ-LIM domain-containing protein 2 (PDLIM2) regulates cell polarity and the protein stability of key transcription factors in epithelial and hemopoietic cells. We previously reported that PDLIM2 is more highly expressed in Triple Negative Breast Cancer (TNBC) than in other breast cancer types or normal breast tissue. In the course of the TNBC study, it was noted that PDLIM2 was highly expressed in the stroma of PDLIM2-expressing tumours.

PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer.

The PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an epithelial-to-mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of nontransformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis.

FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion.

IGF-1 receptor (IGF-1R) and integrin cooperative signaling promotes cancer cell survival, proliferation, and motility, but whether this influences cancer progression and therapy responses is largely unknown. Here we investigated the non-receptor tyrosine adhesion kinase FES-related (FER), following its identification as a potential mediator of sensitivity to IGF-1R kinase inhibition in a functional siRNA screen. We found that FER and the IGF-1R co-locate in cells and can be co-immunoprecipitated.

IGF-1 Receptor and Adhesion Signaling: An Important Axis in Determining Cancer Cell Phenotype and Therapy Resistance.

IGF-1R expression and activation levels generally cannot be correlated in cancer cells, suggesting that cellular proteins may modulate IGF-1R activity. Strong candidates for such modulation are found in cell-matrix and cell-cell adhesion signaling complexes. Activated IGF-1R is present at focal adhesions, where it can stabilize β1 integrin and participate in signaling complexes that promote invasiveness associated with epithelial mesenchymal transition (EMT) and resistance to therapy.

Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-integrin-RhoA signaling axis.

PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB) and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT). PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells.

PDLIM2 regulates transcription factor activity in epithelial-to-mesenchymal transition via the COP9 signalosome.

Epithelial cell differentiation and polarized migration associated with epithelial-to-mesenchymal transition (EMT) in cancer requires integration of gene expression with cytoskeletal dynamics. Here we show that the PDZ-LIM domain protein PDLIM2 (Mystique/SLIM), a known cytoskeletal protein and promoter of nuclear nuclear factor κB (NFκB) and signal transducer and activator of transcription (STAT) degradation, regulates transcription factor activity and gene expression through the COP9 signalosome (CSN). Although repressed in certain cancers, PDLIM2 is highly expressed in invasive cancer cells.

c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 and by disruption of actin.

Inhibition of integrins alphavbeta3 and alphavbeta5 in human brain microvascular endothelial cells (HBMECs) by the function-blocking peptide RGDfV induces loss of spreading on vitronectin, cell detachment, and apoptosis. We demonstrate that cell detachment is not required for apoptosis because plating on bovine serum albumin-blocked poly-L-lysine (allows attachment, but not integrin ligation and cell spreading) also induced apoptosis. Latrunculin B (LatB), which inhibits F-actin polymerization, induced transient loss of HBMEC spreading on vitronectin, but not their detachment, and induced apoptosis despite recovery of cell spreading.

Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H+-ATPase to control endosomal pH and receptor trafficking.

Endocytosis and trafficking of receptors and nutrient transporters are dependent on an acidic intra-endosomal pH that is maintained by the vacuolar H(+)-ATPase (V-ATPase) proton pump. V-ATPase activity has also been associated with cancer invasiveness. Here, we report on a new V-ATPase-associated protein, which we identified in insulin-like growth factor I (IGF-I) receptor-transformed cells, and which was separately identified in Caenorhabditis elegans as HRG-1, a member of a family of heme-regulated genes.

Effect of reproductive status on uptake of latex microparticles in rat small intestine.

This study investigates whether pregnancy or lactation affects microparticle uptake across the small intestinal mucosal barrier, since aspects of gastrointestinal physiology such as motility may be altered in these conditions. It also reports on validation of the model by several methods and discusses the findings in relation to possible mechanisms. Anaesthetised, pregnant, lactating, virgin female or male adult rats were gavaged with fluorescent latex microparticles.

Endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 involves ceramide metabolic pathways.

Matrix ligation of integrins alphavbeta3/alphavbeta5 is critical for endothelial survival and angiogenesis. We have previously shown that ceramide, a proapoptotic lipid second messenger, increases during endothelial anoikis (detachment-induced apoptosis). We now show that RGDfV, an integrin alphavbeta3/alphavbeta5 cyclic function-blocking peptide, increased ceramide and decreased sphingomyelin in human brain microvascular endothelial cells (HBMECs) plated on vitronectin, suggesting that sphingomyelin hydrolysis contributes to RGDfV-induced ceramide increase.

Sources of PDGF expression in murine retina and the effect of short-term diabetes.

Purpose: Progressive dysfunction and death of vascular smooth muscle cells and pericytes is a pathophysiological hallmark of diabetic retinopathy, although the underlying mechanisms behind this process remain ill-defined. The multifunctional peptide platelet-derived growth factor (PDGF) is known to act as an important survival factor for both of these vascular cell-types at times of physiological stress. The retinal cell source(s) of PDGF remain unknown.