title: Alternative splicing results in RET isoforms with distinct trafficking properties.
abstract: RET encodes a receptor tyrosine kinase that is essential for spermatogenesis, development of the sensory, sympathetic, parasympathetic, and enteric nervous systems and the kidneys, as well as for maintenance of adult midbrain dopaminergic neurons. RET is alternatively spliced to encode multiple isoforms that differ in their C-terminal amino acids. The RET9 and RET51 isoforms display unique levels of autophosphorylation and have differential interactions with adaptor proteins. They induce distinct gene expression patterns, promote different levels of cell differentiation and transformation, and play unique roles in development. Here we present a comprehensive study of the subcellular localization and trafficking of RET isoforms. We show that immature RET9 accumulates intracellularly in the Golgi, whereas RET51 is efficiently matured and present in relatively higher amounts on the plasma membrane. RET51 is internalized faster after ligand binding and undergoes recycling back to the plasma membrane. This differential trafficking of RET isoforms produces a more rapid and longer duration of signaling through the extracellular-signal regulated kinase/mitogen-activated protein kinase pathway downstream of RET51 relative to RET9. Together these differences in trafficking properties contribute to some of the functional differences previously observed between RET9 and RET51 and establish the important role of intracellular trafficking in modulating and maintaining RET signaling.
authors.affiliation: Department of Pathology and Molecular Medicine and Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON, Canada.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Richardson
authors.forename: David M
authors.initials: DM
authors.lastname: Rodrigues
authors.forename: Brandy D
authors.initials: BD
authors.lastname: Hyndman
authors.forename: Mathieu J F
authors.initials: MJ
authors.lastname: Crupi
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Nicolescu
authors.forename: Lois M
authors.initials: LM
authors.lastname: Mulligan
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D018920:Coculture Techniques; D011992:Endosomes / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D020033:Protein Isoforms; D051096:Proto-Oncogene Proteins c-ret; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C099282:RET protein, human