The activation loop of phosphatidylinositol phosphate kinases determines signaling specificity

Mol Cell. 2000 Jan;5(1):1-11. doi: 10.1016/s1097-2765(00)80398-6.


Phosphatidylinositol-4,5-bisphosphate plays a pivotal role in the regulation of cell proliferation and survival, cytoskeletal reorganization, and membrane trafficking. However, little is known about the temporal and spatial regulation of its synthesis. Higher eukaryotic cells have the potential to use two distinct pathways for the generation of phosphatidylinositol-4,5-bisphosphate. These pathways require two classes of phosphatidylinositol phosphate kinases, termed type I and type II PIP kinases. While highly related by sequence, these kinases localize to different subcellular compartments, phosphorylate distinct substrates, and are functionally nonredundant. Here, we show that a 20- to 25-amino acid loop spanning the catalytic site, termed the activation loop, determines both enzymatic specificity and subcellular targeting of PIP kinases. Therefore, the activation loop controls signaling specificity and PIP kinase function at multiple levels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans
  • Cell Membrane / enzymology*
  • Drosophila melanogaster
  • Enzyme Activation
  • Escherichia coli
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphatidylinositols / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Conformation
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Saccharomyces cerevisiae
  • Schizosaccharomyces
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Transfection
  • Tumor Cells, Cultured


  • Isoenzymes
  • Phosphatidylinositols
  • Recombinant Fusion Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase