Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development.
The Claudin-like protein of 24 kDa (CLP24) is a hypoxia-regulated transmembrane protein of unknown function. We show here that clp24 knockdown in Danio rerio and Xenopus laevis results in defective lymphatic development. Targeted disruption of Clp24 in mice led to enlarged lymphatic vessels having an abnormal smooth muscle cell coating. We also show that the Clp24(-/-) phenotype was further aggravated in the Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds and that CLP24 interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGFR-3 and attenuates the transcription factor CREB phosphorylation via these receptors. Our results indicate that CLP24 is a novel regulator of VEGFR-2 and VEGFR-3 signaling pathways and of normal lymphatic vessel structure.
Saharinen
Pipsa
P
Molecular/Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki FIN-00014, Finland.
Helotera
Hanna
H
Miettinen
Juho
J
Norrmen
Camilla
C
D'Amico
Gabriela
G
Jeltsch
Michael
M
Langenberg
Tobias
T
Vandevelde
Wouter
W
Ny
Annelii
A
Dewerchin
Mieke
M
Carmeliet
Peter
P
Alitalo
Kari
K
D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D042601:Lymphatic Vessels / Q000196:embryology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
D008565:Membrane Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3