RESUMEN

The ErbB2 receptor tyrosine kinase plays a key role in mammary gland development. It forms large clusters which serve as signaling platforms for integration of extracellular information. The discoidin domain receptor (DDR) family are collagen receptor tyrosine kinases which, together with ErbB2, are involved in many physiological and pathological processes. Here, we investigated the interaction of ErbB2 and DDR1 receptors in breast cancer cells. In contrast to beta1-integrin, DDR1 colocalizes with ErbB2 in membrane clusters regardless of their expression levels. We demonstrated that this spatial coexistence is a consequence of the physical interaction between these receptors. In addition, these receptors are coexpressed in the normal mammary gland but not in breast tumor samples. Together, these results present DDR1 as a novel modulator of the ErbB2/ErbB3 signaling pathway.

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RESUMEN

Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by ß-oxidation or used in phospholipids' synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

RESUMEN

ErbB2 is a member of the ErbB family of tyrosine kinase receptors that plays a major role in breast cancer progression. Located at the plasma membrane, ErbB2 forms large clusters in spite of the presence of growth factors. Beta1 integrin, membrane receptor of extracellular matrix proteins, regulates adhesion, migration and invasiveness of breast cancer cells. Physical interaction between beta1 integrin and ErbB2 has been suggested although published data are contradictory. The aim of the present work was to study the interaction between ErbB2 and beta1 integrin in different scenarios of expression and activation. We determined that beta1 integrin and ErbB2 colocalization is dependent on the expression level of both receptors exclusively in adherent cells. In suspension cells, lack of focal adhesions leave integrins free to diffuse on the plasma membrane and interact with ErbB2 even at low expression levels of both receptors. In adherent cells, high expression of beta1 integrin leaves unbound receptors outside focal complexes that diffuse within the plasma membrane and interact with ErbB2 membrane domains. Superresolution imaging showed the existence of two distinct populations of ErbB2: a major population located in large clusters and a minor population outside these structures. Upon ErbB2 overexpression, receptors outside large clusters can freely diffuse at the membrane and interact with integrins. These results reveal how expression levels of beta1 integrin and ErbB2 determine their frequency of colocalization and show that extracellular matrix proteins shape membrane clusters distribution, regulating ErbB2 and beta1 integrin activity in breast cancer cells.

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