Cable Cars to the Nucleus: TM4SF1-Enriched Microdomains Conduct Signaling in Endothelial Cells for Blood Vessel Formation

Endothelial cell proliferation, migration, and intercellular interactions for blood vessel formation require coordinated signaling by a myriad of molecules. Following endothelial cell activation by growth factors and cytokines, a variety of signaling molecules are activated on the surface and transported intracellularly by TM4SF1-enriched microdomains (TMEDs), 100-300 nm diameter protein-lipid complexes recruited by the transmembrane protein TM4SF1. TMEDs internalize via microtubules from the cell surface toward the microtubule-organizing center (MTOC) and then enter the nucleus via nuclear pores (see Graphic Illustration). This internalization pathway permits delivery of activated proteins and other signaling molecules from the cell surface to the nucleus, which directly translates extracellular stimuli to modulation of gene expression. Molecules transported by this route include phospholipase C, gamma 1 (PLCγ1), histone deacetylase 6 (HDAC6), and importins. In the absence of TMEDs, endothelial cells lose the ability to divide into cultures in vitro and to support blood vessel formation in mouse embryos in vivo. We liken TMEDs to cable cars, which take in passengers at the cell surface, travel along microtubule cables, and deliver their passengers to various locations, including the "city center", the nucleus. This commentary aims to elucidate the functions of TMEDs in endothelial cells, to show that cells, like busy cities, need efficient transport systems to deliver molecules to the destinations where they perform their cellular functions. TMEDs offer a novel and curated transport system providing selected molecules with access to the nucleus.