title: Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity.
abstract: We describe here the tyrosine kinase activity of human biliverdin reductase (BVR) and its potential role in the insulin-signaling pathway. BVR is both a substrate for insulin receptor (IR) tyrosine kinase (IRK) activity and a kinase for serine phosphorylation of IR substrate 1 (IRS-1). Our previous studies have revealed serine/threonine kinase activity of BVR. Y198, in the YMKM motif found in the C-terminal domain of BVR, is shown to be a substrate for insulin-activated IRK. This motif in IRS proteins provides a docking site for proteins that contain a Src homology 2 domain. Additionally, Y228 in the YLSF sequence and Y291 are IRK substrates; the former sequence provides optimum recognition motif in the tyrosine phosphatase, SHP-1, and for SHC (Src homology 2 domain containing transfroming protein 1). BVR autophosphorylates N-terminal tyrosines Y72 and Y83. Serine residues in IRS-1 are targets for BVR phosphorylation, and point mutation of serine residues in the kinase domain of the reductase inhibits phosphotransferase activity. Because tyrosine phosphorylation of IRS-1 activates the insulin signaling pathway and serine phosphorylation of IRS-1 blocks insulin action, our findings that insulin increases BVR tyrosine phosphorylation and that there is an increase in glucose uptake in response to insulin when expression of BVR is "knocked down" by small interfering RNA suggest a potential role for BVR in the insulin signaling pathway.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14624, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lerner-Marmarosh
authors.forename: Jenny
authors.initials: J
authors.lastname: Shen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Torno
authors.forename: Anatoliy
authors.initials: A
authors.lastname: Kravets
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Hu
authors.forename: Mahin D
authors.initials: MD
authors.lastname: Maines
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D001786:Blood Glucose; D004926:Escherichia coli; D005822:Genetic Vectors; D005982:Glutathione Transferase; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D034741:RNA, Small Interfering; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases