Removal of cell surface heparan sulfate increases TACE activity and cleavage of ErbB4 receptor.
BACKGROUND
Nuclear localization of proteolytically formed intracellular fragment of ErbB4 receptor tyrosine kinase has been shown to promote cell survival, and nuclear localization of ErbB4 receptor has been described in human breast cancer. Tumor necrosis factor alpha converting enzyme (TACE) initiates the proteolytic cascade leading to ErbB4 intracellular domain formation. Interactions between matrix metalloproteases and heparan sulfate have been described, but the effect of cell surface heparan sulfate on TACE activity has not been previously described.


RESULTS
As indicated by immunodetection of increased ErbB4 intracellular domain formation and direct enzyme activity analysis, TACE activity was substantially amplified by enzymatic removal of cell surface heparan sulfate but not chondroitin sulfate.


CONCLUSIONS
In this communication, we suggest a novel role for cell surface heparan sulfate. Removal of cell surface heparan sulfate led to increased formation of ErbB4 intracellular domain. As ErbB4 intracellular domain has previously been shown to promote cell survival this finding may indicate a novel mechanism how HS degradation active in tumor tissue may favor cell survival.
Määttä
Jorma A
JA
Turku Center for Disease Modeling/Department of Cell Biology and Anatomy, University of Turku, Turku, Finland. jmaatta@utu.fi
Olli
Kaisa
K
Henttinen
Tiina
T
Tuittila
Minna T
MT
Elenius
Klaus
K
Salmivirta
Markku
M
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry*; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066246:ErbB Receptors; D006497:Heparan Sulfate; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C000606462:ADAM17 protein, human