Importantly then, cargos take charge of their own destiny and play an active role in their own trafficking

by recruiting specific regulators. To use an analogy, cargos are often less like passengers on a subway train with a predetermined route, but more like taxi cab riders who direct the driver where to go. For many receptor classes, signaling is not restricted to the plasma membrane. Rather, upon ligand binding, the receptor is internalized and continues to signal from endosomes Selleckchem AG 14699 (Cosker et al., 2008, Murphy et al., 2009, Platta and Stenmark, 2011 and Sadowski et al., 2009). Often, the signals generated in endosomes are distinct from those generated at the plasma membrane (Figure 2), due to the endosomal localization of signaling components (for review, see Hupalowska and Miaczynska, 2012, Murphy et al., 2009 and Dobrowolski and De Robertis, 2012). This mechanism was first demonstrated for EGF receptor signaling in cell lines (Vieira et al., 1996), and it is now known that similar signaling on endosomes occurs for other tyrosine

kinases, including Trks, which play crucial roles in the nervous system (Cosker et al., 2008, Howe and Mobley, 2004 and Ibáñez, 2007). G protein-coupled receptors also signal from endosomes. β-arrestin-mediated endocytosis of GPCRs into endosomes recruits G protein-independent signaling PI3K inhibitor components and elicits additional signaling in endosomes. Depending on the particular GPCR, β-arrestin affinity varies, thereby, changing the extent and nature of signaling (for review, see Murphy et al., 2009). The entry route of receptors during endocytosis can also influence the subsequent endosomal trafficking and the nature

of endosomal signaling. TGF-β receptors, for instance, can enter cells either via clathrin-mediated endocytosis or via clathrin-independent caveolar endocytosis (Di Guglielmo et al., 2003 and Le Roy and Wrana, Dipeptidyl peptidase 2005). When entering through caveolae, activated TGF-β receptors associate with Smad7 and Smurf2 and enter a degradative endosomal compartment. When entering through clathrin-mediated endocytosis, TGF-β receptors associate with Sara and Smad2 and elicit signaling in early endosomes. Endosomes are thus essential locales for signal transduction. The term “signaling endosomes” has been coined for the retrogradely transporting endosomes containing activated neurotrophin receptors (Howe and Mobley, 2004), but arguably many different kinds of signaling endosomes can be generated by different ligand/receptor system and result in a large range of different signaling responses. Much work is still needed to understand the kinds of signaling endosomes generated downstream of different receptors and their regulation.