Trk-signaling endosomes are generated by Rac-dependent macroendocytosis.
Why neurotrophins and their Trk receptors promote neuronal differentiation and survival whereas receptor tyrosine kinases for other growth factors, such as EGF, do not, has been a long-standing question in neurobiology. We provide evidence that one difference lies in the selective ability of Trk to generate long-lived signaling endosomes. We show that Trk endocytosis is distinguished from the classical clathrin-based endocytosis of EGF receptor (EGFR). Although Trk and EGFR each stimulate membrane ruffling, only Trk undergoes both selective and specific macroendocytosis at ruffles, which uniquely requires the Rho-GTPase, Rac, and the trafficking protein, Pincher. This process leads to Trk-signaling endosomes, which are immature multivesicular bodies that retain Rab5. In contrast, EGFR endosomes rapidly exchange Rab5 for Rab7, thereby transiting into late-endosomes/lysosomes for degradation. Sustained endosomal signaling by Trk does not reflect intrinsic differences between Trk and EGFR, because each elicits long-term Erk-kinase activation from the cell surface. Thus, a population of stable Trk endosomes, formed by specialized macroendocytosis in neurons, provides a privileged endosome-based system for propagation of signals to the nucleus.
Valdez
Gregorio
G
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794-5230, USA.
Philippidou
Polyxeni
P
Rosenbaum
Julie
J
Akmentin
Wendy
W
Shao
Yufang
Y
Halegoua
Simon
S
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D066246:ErbB Receptors; D020917:Receptor, trkA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020696:rab5 GTP-Binding Proteins; D020744:rac GTP-Binding Proteins