Figure 1. Regulation of cell migration by signaling endosomes. Leading edge: Cellular polarization, formation of the cell protrusion, lamellipodia and circular ruffles are controlled by the small GTPases Cdc42 and Rac. They are transported toward the plasma membrane on early endosomes in an Arf6-dependent manner. Activation of Cdc42 and Rac involves endosomal association of their GEFs, αPIX and Tiam1, respectively. Src moves on early endosomes toward focal adhesions. PTPD1 localizes to early, late and recycling endosomes upon EGF receptor endocytosis. Late endosomes carrying p14/MP1 MAPK scaffold complex can target focal adhesion and serve as a signaling platform for MAPK pathway (lower panel). Trailing edge: Focal adhesion disassembly requires integrin endocytosis and acto-myosin contractility. Integrins are endocytosed into early endosomes and are further recycled back to the leading edge to form new adhesions. Acto-myosin contractility is locally regulated by Endo180-carrying early endosomes through Rho-ROCK-MLC pathway and potentially through p14/MP1 late endosomes (lower panel).