CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations

Neurogenetics. 2007 Nov;8(4):249-56. doi: 10.1007/s10048-007-0098-9. Epub 2007 Jul 27.

Abstract

Individuals carrying a mutation in one of the three cerebral cavernous malformation genes (CCM1/KRIT1, CCM2, CCM3) cannot be clinically distinguished, raising the possibility that they act within common molecular pathways. In this study, we demonstrate that CCM3 (PDCD10) coprecipitates and colocalizes with CCM2. We also show that CCM3 directly binds to serine/threonine kinase 25 (STK25, YSK1, SOK1) and the phosphatase domain of Fas-associated phosphatase-1 (FAP-1, PTPN13, PTP-Bas, PTP-BL). CCM3 is phosphorylated by STK25 but not by its other Yeast-Two hybrid interactor STK24, whereas the C-terminal catalytic domain of FAP-1 dephosphorylates CCM3. Finally, our experiments reveal that STK25 forms a protein complex with CCM2. Thus, our data link two proteins of unknown function, CCM3 and STK25, with CCM2, which is part of signaling pathways essential for vascular development and CCM pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line
  • Germ-Line Mutation
  • Hemangioma, Cavernous, Central Nervous System / etiology
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Hemangioma, Cavernous, Central Nervous System / metabolism
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Two-Hybrid System Techniques

Substances

  • Apoptosis Regulatory Proteins
  • CCM2 protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • PDCD10 protein, human
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Protein-Serine-Threonine Kinases
  • STK25 protein, human
  • PTPN13 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13