title: Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases.
abstract: Intracellular localization has been reported for over three-quarters of receptor tyrosine kinase (RTK) families in response to environmental stimuli. Internalized RTK may bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by γ-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperone or transcription factors, while membrane-bound RTKs (full-length or truncated) are transported from the plasma membrane to the ER through the well-established Rab- or clathrin adaptor protein-coated vesicle retrograde trafficking pathways. Subsequent nuclear transport of membrane-bound RTK may occur via two pathways, INFS or INTERNET, with the former characterized by release of receptors from the ER into the cytosol and the latter characterized by release of membrane-bound receptor from the ER into the nucleoplasm through the inner nuclear membrane. Although most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking and nuclear functions of RTKs, and discuss how they promote cancer progression, and their clinical implications.
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mei-Kuang
authors.initials: MK
authors.lastname: Chen
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center of Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D017398:Alternative Splicing; D002462:Cell Membrane / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: INTERNET; MRIN; RTK cleavage; intracellular trafficking; non-canonical RTK functions; nuclear receptor tyrosine kinases; nuclear translocation; proteolytic cleavage; receptor tyrosine kinase; retrograde trafficking