title: HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop.
abstract: The multitude of mechanisms regulating the activity of protein kinases includes phosphorylation of amino acids contained in the activation loop. Here we show that the serine/threonine kinase HIPK2 (homeodomain-interacting protein kinase 2) is heavily modified by autophosphorylation, which occurs by cis-autophosphorylation at the activation loop and by trans-autophosphorylation at other phosphorylation sites. Cis-autophosphorylation of HIPK2 at Y354 and S357 in the activation loop is essential for its kinase function and the binding to substrates and the interaction partner Pin1. HIPK2 activation loop phosphorylation is also required for its biological activity as a regulator of gene expression and cell proliferation. Phosphorylation of HIPK2 at Y354 alone is not sufficient for full HIPK2 activity, which is in marked contrast to some dual-specificity tyrosine-phosphorylated and regulated kinases where tyrosine phosphorylation is absolutely essential. This study shows that differential phosphorylation of HIPK2 provides a mechanism for controlling and specifying the signal output from this kinase.
authors.affiliation: Department of Biochemistry, Medical Faculty,  Justus Liebig University,  Member of the German Center for Lung Research, Friedrichstrasse 24, Giessen 35392,  Germany.
authors.forename: Vera V
authors.initials: VV
authors.lastname: Saul
authors.forename: Laureano
authors.initials: L
authors.lastname: de la Vega
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Karin
authors.initials: K
authors.lastname: Fritz-Wolf
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases