14-3-3 sigma associates with cell surface aminopeptidase N in the regulation of matrix metalloproteinase-1.
Matrix metalloproteinases (MMPs) are implicated in the degradation of the extracellular matrix during development and tissue repair, as well as in pathological conditions such as tumor invasion and fibrosis. MMP expression by stromal cells is partly regulated by signals from the neighboring epithelial cells. Keratinocyte-releasable 14-3-3sigma, or stratifin, acts as a potent MMP-1-stimulatory factor in fibroblasts. However, its mechanism of transmembrane signaling remains unknown. Ectodomain biotin labeling, serial affinity purification and mass spectroscopy analysis revealed that the stratifin associates with aminopeptidase N (APN), or CD13, at the cell surface. The transient knockdown of APN in fibroblasts eliminated the stratifin-mediated p38 MAP kinase activation and MMP-1 expression, implicating APN in a receptor-mediated transmembrane signaling event. Stratifin deletion studies implicated its C-terminus as a potential APN-binding site. Furthermore, the dephosphorylation of APN ectodomains reduced its binding affinity to the stratifin. The presence of a phosphorylated serine or threonine residue in APN has been implicated. Together, these findings provide evidence that APN is a novel cell surface receptor for stratifin and a potential target in the regulation of MMP-1 expression in epithelial-stromal cell communication.
Ghaffari
Abdi
A
Department of Surgery, BC Professional Firefighter's Burn and Wound Healing Research Laboratory, University of British Columbia, 344A JBRC, 2660 Oak Street, Vancouver, Canada, BC V6H 3Z6.
Li
Yunyaun
Y
Kilani
Ruhangiz T
RT
Ghahary
Aziz
A
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D041702:BALB 3T3 Cells; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018826:CD13 Antigens / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005092:Exonucleases / Q000378:metabolism*; D005095:Exoribonucleases; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013058:Mass Spectrometry; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D011817:Rabbits; D015398:Signal Transduction
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D018826:CD13 Antigens; D020781:Matrix Metalloproteinase 1