2. Academic Validation
  3. TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation

TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation

  • J Exp Med. 2026 May 4;223(5):e20251374. doi: 10.1084/jem.20251374.
Lun Li 1 2,  Marco Castro 3 4,  Hiroki Hongo 1 5,  Jian Ren 1 6,  Robert Shenkar 7,  Rashad Jabarkheel 1 2,  Siqi Gao 1,  Sweta Narayan 1,  Maxwell Frankfurter 1,  Alan T Tang 1,  Jisheng Yang 1,  Mei Chen 1,  Jenna Bockman 1,  Patricia Mericko-Ishizuka 1,  Roberto Alcazar 7,  Georgio Sader 7,  Javed Iqbal 7,  Serena Kinkade 7,  Rhonda Lightle 7,  Andrew K Ressler 8,  Xianghu Qu 9,  H Scott Baldwin 9,  Douglas A Marchuk 8,  Issam A Awad 7,  Jan-Karl Burkhardt 2,  Michael Potente 3 4,  Mark L Kahn 1
Affiliations

Affiliations

  • 1 Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of Neurosurgery, Perelman School of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Angiogenesis & Metabolism Laboratory, Center of Vascular Biomedicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin , Berlin, Germany.
  • 4 Max Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin, Germany.
  • 5 Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • 6 Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, National Center for Neurological Disorders, Capital Medical University, Beijing, China.
  • 7 Department of Surgery, Neurovascular Surgery Program, Section of Neurosurgery, Medicine and Biological Sciences, The University of Chicago, Chicago, IL, USA.
  • 8 Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC, USA.
  • 9 Division of Pediatrics Cardiology, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
PMID: 41891922 DOI: 10.1084/jem.20251374
Abstract

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and Tie2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of Tie2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic Tie2 blockade in mouse models. Our studies identify Tie2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting Tie2 may be an effective means to treat human CCM disease.

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