Direct stimulation of ERBB2 highlights a novel cytostatic signaling pathway driven by the receptor Thr phosphorylation.

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor.

Inflammatory Response Modulation through a PPARγ Agonist during Surgically Induced Visceral Ischemia in an Animal Model.

Background: Ischemia/reperfusion (I/R) injury represents one of the most severe complications in vascular surgery where cross-clamping of the aorta and subsequent visceral ischemia are a recurrent issue. The literature describes a family of nuclear receptors, that is, peroxisome proliferator-activated receptors (PPARs), in particular PPARγ isoform, which are important modulators of vascular inflammation resulting from I/R injury. The aim of our study is to evaluate how PPARγ agonist administration could reduce local and systemic inflammatory response after I/R injury during aortic supraceliac clamping in animal model.

Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells.

ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade.

Melanosome-autonomous regulation of size and number: the OA1 receptor sustains PMEL expression.

Little is known as to how cells ensure that organelle size and number are coordinated to correctly couple organelle biogenesis to the demands of proliferation or differentiation. OA1 is a melanosome-associated G-protein-coupled receptor involved in melanosome biogenesis during melanocyte differentiation. Cells lacking OA1 contain fewer, but larger, mature melanosomes.

The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments.

The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial.

The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells.

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery.

Molecular interactions with obscurin are involved in the localization of muscle-specific small ankyrin1 isoforms to subcompartments of the sarcoplasmic reticulum.

We report here on experiments aimed to characterise the molecular basis of the interactions between muscle-specific ankyrin1 isoforms localized on the sarcoplasmic reticulum and obscurin a protein associated with the contractile apparatus. A novel small muscle-specific ankyrin isoform, ank1.9 was identified that, similarly to the known ank1.

An unconventional dileucine-based motif and a novel cytosolic motif are required for the lysosomal and melanosomal targeting of OA1.

The protein product of the gene responsible for ocular albinism type 1, named OA1, is a pigment-cell-specific membrane glycoprotein, displaying features of G-protein-coupled receptors, yet exclusively localized to late endosomes, lysosomes and melanosomes. To dissect the signals responsible for the intracellular localization of OA1, we generated chimeric proteins consisting of the cytosolic domains of OA1 fused to the lumenal and transmembrane domains of LAMP1; in addition, we generated missense and deletion mutants of full-length OA1. Using this approach, we identified two separate sorting signals that are both necessary and sufficient for intracellular retention, as well as lysosomal and melanosomal localization, in melanocytic and non-melanocytic cells.

The melanosomal/lysosomal protein OA1 has properties of a G protein-coupled receptor.

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific integral membrane glycoprotein, localized to melanosomes and lysosomes and possibly implicated in melanosome biogenesis. Although its function remains unknown, we previously showed that OA1 shares structural similarities with G protein-coupled receptors (GPCRs). To ascertain the molecular function of OA1 and in particular its nature as a GPCR, we adopted a heterologous expression strategy commonly exploited to demonstrate GPCR-mediated signaling in mammalian cells.

Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles.

Assembly of specialized membrane domains, both of the plasma membrane and of the ER, is necessary for the physiological activity of striated muscle cells. The mechanisms that mediate the structural organization of the sarcoplasmic reticulum with respect to the myofibrils are, however, not known. We report here that ank1.