title: Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation.
abstract: Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Kong
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Lange
authors.forename: Dmitri
authors.initials: D
authors.lastname: Samovski
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.forename: Jialiu
authors.initials: J
authors.lastname: Liu
authors.forename: Sinju
authors.initials: S
authors.lastname: Sundaresan
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stahl
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
chemical_list: C506299:CUL7 protein, human; D044842:Cullin Proteins; D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; C467563:TBC1D3 protein, human; D003545:Cysteine