title: Prointerleukin-16 contains a functional CcN motif that regulates nuclear localization.
abstract: The immunomodulatory cytokine interleukin-16 (IL-16) represents the secreted C-terminus of a larger precursor, pro-IL-16. Following cleavage by caspase 3, the residual N-terminal domain translocates into the nucleus, inducing G(0)/G(1) cell cycle arrest. We have previously identified a classical bipartite nuclear localization sequence (NLS) in the N-terminal domain of pro-IL-16. We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. This is the first description of a functional CcN motif in a cytokine precursor.
authors.affiliation: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA. KWilson@lung.bumc.bu.edu
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Wilson
authors.forename: William W
authors.initials: WW
authors.lastname: Cruikshank
authors.forename: David M
authors.initials: DM
authors.lastname: Center
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D047390:Casein Kinase II; D002522:Chlorocebus aethiops; D016193:G1 Phase / Q000235:genetics; D006801:Humans; D019410:Interleukin-16 / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics; D014162:Transfection
chemical_list: D019410:Interleukin-16; D019913:Nuclear Localization Signals; D010446:Peptide Fragments; D011498:Protein Precursors; C105950:interleukin 16 precursor; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase