title: TrkA in vivo function is negatively regulated by ubiquitination.
abstract: TrkA is a tyrosine kinase receptor required for development and survival of the peripheral nervous system. In the adult, TrkA and its ligand NGF are peripheral pain mediators, particularly in inflammatory pain states. However, how TrkA regulates the function of nociceptive neurons and whether its activity levels may lead to sensory abnormalities is still unclear. Here we report the characterization of a 3 aa (KFG) domain that negatively regulates TrkA level and function in response to NGF. Deletion of this domain in mouse causes a reduction of TrkA ubiquitination leading to an increase in TrkA protein levels and activity. The number of dorsal root ganglia neurons is not affected by the mutation. However, mutant mice have enhanced thermal sensitivity and inflammatory pain. Together, these data suggest that ubiquitination is a mechanism used in nociceptive neurons to regulate TrkA level and function. Our results may enhance our understanding of how ubiquitination affects TrkA activation following noxious thermal stimulation and inflammatory pain.
authors.affiliation: Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, Department of Target Discovery and Experimental Microbiology, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, University of Maryland School of Nursing and Program in Neuroscience, Baltimore, Maryland 21201, and Department of MVIMG, Wexner Medical Center Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Erkan
authors.initials: E
authors.lastname: Kiris
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Sudhirkumar
authors.initials: S
authors.lastname: Yanpallewar
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.forename: Jodi
authors.initials: J
authors.lastname: Becker
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Palko
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009619:Nociceptors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA