New insights into the regulation of ion channels by integrins.

By controlling cell adhesion to the extracellular matrix, integrin receptors regulate processes as diverse as cell migration, proliferation, differentiation, apoptosis, and synaptic stability. Because the underlying mechanisms are generally accompanied by changes in transmembrane ion flow, a complex interplay occurs between integrins, ion channels, and other membrane transporters. This reciprocal interaction regulates bidirectional signal transduction across the cell surface and may take place at all levels of control, from transcription to direct conformational coupling. In particular, it is becoming increasingly clear that integrin receptors form macromolecular complexes with ion channels. Besides contributing to the membrane localization of the channel protein, the integrin/channel complex can regulate a variety of downstream signaling pathways, centered on regulatory proteins like tyrosine kinases and small GTPases. In turn, the channel protein usually controls integrin activation and expression. We review some recent advances in the field, with special emphasis on hematology and neuroscience. Some oncological implications are also discussed.

Stable GM3 lactone mimetic raises antibodies specific for the antigens expressed on melanoma cells.

Immunotherapy of tumors and of melanoma in particular has a long history, and recently this therapeutic approach found a reliable scientific rationale. This biological therapy aims to teach the patient's immune system to recognize the antigens expressed on tumor cells and destroy them, leaving normal cells intact. The success of this therapy highly depends on the selection of target antigens that are essential for tumors growth and progression. The overexpression of GM(3) ganglioside 1 and especially the expression of its metabolite GM(3) lactone 2 characterize murine and human melanomas, playing an important role in tumor progression and making such self-antigens potential targets for the immunotherapy of these neoplasms. Although more immunogenic than its precursor, GM(3) lactone 2 is unsuitable to be used in immunotherapy as a melanoma-associated antigen (MAA) because it is unstable under physiological conditions. We designed and synthesized the hydrolytically stable mimetic 3, which is remarkably simpler than the native lactone 2; after conjugation of 3 to the protein carrier keyhole-limpet hemocyanin (KLH), the obtained glycoprotein 5 was used as the immunogen in vivo to successfully elicit specific antimelanoma antibodies. In fact, no appreciable binding to GM(1) was observed. Capitalizing on the stability and on the reduced structural complexity of mimetic 3, the immunostimulant 5 we report represents a new promising synthetic glycoconjugate for the immunotherapy of melanoma.