T-cadherin mediates low-density lipoprotein-initiated cell proliferation via the Ca(2+)-tyrosine kinase-Erk1/2 pathway.
The GPI-anchored protein T-cadherin was found to be an atypical LDL binding site that is expressed in various types of cells, including endothelial cells, smooth muscle cells, and neurons. Notably, the expression of T-cadherin was reduced in numerous types of cancers, although it was up-regulated in tumor-penetrating blood vessels, atherosclerotic lesions, and during neointima formation. Despite these intriguing findings, our knowledge of the physiological role and the signal transduction pathways associated with this protein is limited. Therefore, T-cadherin was overexpressed in the human umbilical vein-derived endothelial cell line EA.hy926, the human embryonic kidney cell line HEK293, and LDL-initiated signal transduction, and its consequences were elucidated. Our data revealed that T-cadherin serves as a receptor specifically for LDL. Following LDL binding to T-cadherin, mitogenic signal transduction was initiated that involved activation of PLC and IP3 formation, which subsequently yielded intracellular Ca2+ mobilization. Downstream to these early phenomena, activation of tyrosine kinase(s) Erk 1/2 kinase, and the translocation of NF kappa B toward the nucleus were found. Finally, overexpression of T-cadherin in HEK293 cells resulted in accelerated cell proliferation in an LDL-dependent manner, although cell viability was not influenced. Because LDL uptake was not facilitated by T-cadherin, our data suggest that T-cadherin serves as a signaling receptor for LDL that facilitates an LDL-dependent mitogenic signal in the vasculature.
Kipmen-Korgun
Dijle
D
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University Graz, Graz, Austria.
Osibow
Karin
K
Zoratti
Cristina
C
Schraml
Elisabeth
E
Greilberger
Joachim
J
Kostner
Gerhard M
GM
Jürgens
Günther
G
Graier
Wolfgang F
WF
D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D005470:Fluorometry; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology
D015820:Cadherins; C099972:H-cadherin; D008077:Lipoproteins, LDL; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium