The cytoplasmic domain of proEGF negatively regulates motility and elastinolytic activity in thyroid carcinoma cells.
The intracellular domains of the membrane-anchoring regions of some precursors of epidermal growth factor (EGF) family members have intrinsic biologic activities. We have determined the role of the human proEGF cytoplasmic domain (proEGFcyt) as part of the proEGF transmembrane-anchored region (proEGFctF) in the regulation of motility and elastinolytic invasion in human thyroid cancer cells. We found proEGFctF to act as a negative regulator of motility and elastin matrix penetration and the presence of proEGFcyt or proEGF22.23 resulted in a similar reduction in motility and elastinolytic migration. This activity was counteracted by EGF-induced activation of EGF receptor signaling. Decreased elastinolytic migratory activity in the presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with decreased secretion of elastinolytic procathepsin L. The presence of proEGFctF and proEGFcyt/proEGF22.23 coincided with the specific transcriptional up-regulation of t-SNARE member SNAP25. Treatment with siRNA-SNAP25 resulted in motility and elastin migration being restored to normal levels. Epidermal growth factor treatment down-regulated SNAP25 protein by activating EGF receptor-mediated proteasomal degradation of SNAP25. These data provide first evidence for an important function of the cytoplasmic domain of the human proEGF transmembrane region as a novel suppressor of motility and cathepsin L-mediated elastinolytic invasion in human thyroid carcinoma cells and suggest important clinical implications for EGF-expressing tumors.
Glogowska
Aleksandra
A
Department of Human Anatomy and Cell Science, Winnipeg, Manitoba, Canada.
Pyka
Janette
J
Kehlen
Astrid
A
Los
Marek
M
Perumal
Paul
P
Weber
Ekkehard
E
Cheng
Sheue-yann
SY
Hoang-Vu
Cuong
C
Klonisch
Thomas
T
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004549:Elastin / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D011498:Protein Precursors; D004815:Epidermal Growth Factor; D004549:Elastin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L