Receptor tyrosine kinase and G-protein coupled receptor signaling and sorting within endosomes.

*DivisionofBiologicalSciencesandCenterforStructuralandFunctionalNeuroscience,UniversityofMontana, Missoula, Montana, USA Department of Microbiology, Montana State University, Bozeman, Montana, USAMany neuroscientists desire to understand events that occurat the synapse. We would like to know in exacting detail howreceptors respond to neurotransmitters and neuropeptides.Unfortunately, some mechanisms such as receptors’ mem-brane trafﬁc and signal transduction are not accessible orpractically studied at synapses in vivo, so model systemsmust be used.Data gleaned invitrofrom neuronsor cell linesin culture using the tools ofcell biology has great value infocusing our views about how receptors behave in vivo;nature is conservative and once mechanisms and rules ofbehavior are established they usually hold true in manydifferent contexts. This review examines the hypothesis thatendosomes form organelles that are specialized for signaltransduction, and casts a wide net ﬁshing for clues from cellbiologyabouthowreceptorsmight dothisataxontips.Manyofthese clues are derived from molecular interactions amonggene products with known roles in signal transduction,membrane trafﬁc, and the cytoskeleton.Not so long ago, investigators who studied signaltransduction, membrane trafﬁc, or the cytoskeleton focusedtheir attention mostly within these individual disciplines.Recently these formerly distinct ﬁelds have become linkedtogether in surprising and marvelous ways. Endocytosis isregulated by signal transduction and signal transduction isinitiated from endosomes. The ﬁrst evidence that receptorinternalization is not solely a mechanism for down-regula-tion and termination ofthe receptor’s signal, that receptorscan signal from endosomes, was provided for epidermalgrowth factor (EGF) and insulin receptors by Bergeron andcolleagues (Baass et al. 1995). It is now widely recognizedthat signaling from both receptor tyrosine kinases (RTKs)and G-protein coupled receptors (GPCRs) occurs in intra-cellular organelles derived from endocytosis (Ceresa andSchmid 2000; Di Fiore and De Camilli 2001; Ferguson2001; McPherson et al. 2001; Wiley and Burke 2001).Receptor signal transduction from intracellular organellesactivates distinct pathways and conveys instructions tospeciﬁc intracellular locations. In neurons, signaling afterendocytosis is a compelling means to convey neurotrophinsignals from the tips of axons to the cell body.RTK signaling from endocytic organellesand the signaling vesicles hypothesisDuring development ofthe nervous system, more neuronsare born than are needed and in mammals there is a selectionfor those which make functional connections. Neurons thatdo not make proper connections activate programmed celldeath; neurons that do connect survive and differentiate.When projecting axons reach their target they receiveinstructions in the form of polypeptide growth factors,including neurotrophins such as nerve growth factor (NGF),which bind to receptors (Trks) at the axon tip. This distalsignal must traverse down the axon, a great distance in somecases, to direct the cell body towards differentiation andaway from programmed cell death. Defects in initiation,reception, or transport ofneurotrophin signals may lead tomany different diseases of congenital cognitive dysfunctionand neurodegeneration (Cooper et al. 2001; Sofroniew .2001). It is thus ofvital importance to understand inmolecular detail the generation, conveyance, intracellularlocation, and downstream targets ofneurotrophin signals.One indication ofthe perceived importance ofneurotrophinsin the development andmaintenance ofthe nervous system isthe number ofrecent reviews covering this ﬁeld, no fewer