Large, recursive membrane platforms are associated to Trop-1, Trop-2, and protein kinase signaling for cell growth.

The transmembrane glycoproteins Trop-1/EpCAM and Trop-2 independently trigger Ca and kinase signals for cell growth and tumor progression. Our findings indicated that Trop-1 and Trop-2 tightly colocalize at macroscopic, ruffle-like protrusions (RLP), that elevate from the cell perimeter, and locally recur over hundreds of seconds. These previously unrecognized elevated membrane regions ≥20-µm-long, up to 1.5 µm high were revealed by Z-stack analysis and three-dimensional reconstruction of signal transducer-hosting plasma membrane regions. Trop-2 stimulates cell growth through a membrane supercomplex that comprises CD9, PKCα, ion pumps, and cytoskeletal components. Our findings indicated that the growth-driving Trop-2 supercomplex assembles at RLP. RLP behaved as sites of clustering of signal transducers, of phosphorylation/activation of growth-driving kinases, as recruitment sites of PKCα and as origin of Ca signaling waves, suggesting RLP to be novel signaling platforms in living cells. RLP were induced by growth factors and disappeared upon growth factor deprivation and β-actin depolymerization, candidating RLP to be functional platforms for high-dimensional signaling for cell growth.