Removal of cell surface heparan sulfate increases TACE activity and cleavage of ErbB4 receptor

Jorma A Määttä,Klaus Elenius,Kaisa Olli,Tiina Henttinen,Markku Salmivirta,Minna T Tuittila

doi:10.1186/1471-2121-10-5

Abstract

BackgroundNuclear 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.ResultsAs 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.ConclusionIn 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.

Highlights

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
In breast cancer nuclear localization of ErbB4 receptor has been demonstrated and nuclear ErbB4 expression has been shown to be associated with unfavorable disease prognosis when compared to membraneous ErbB4 expression [18]. In this communication we describe for the first time that removal of cell surface Heparan sulfate (HS) increases membrane bound ErbB4 80 kDa fragment formation by Tumor necrosis factor alpha converting enzyme (TACE)-like activity
(page number not for citation purposes) http://www.biomedcentral.com/1471-2121/10/5 receptor-ligand binding and phorbol myristyl acetate (PMA) [22] and the cleavage is dependent on TACE activity [6,8]

Summary

Introduction

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. 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. Cell surface proteases take part in cell signaling by i) producing soluble extracellular mediators such as growth factors, chemokines and cytokines from membrane bound precursors [3] and ii) generating intracellular signaling molecules from transmembrane protein receptors [4,5]. One such cell surface protease is tumor necrosis factor alpha (TNF-α) converting enzyme, TACE [3]

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