title: MEK/ERK pathway mediates PKC activation-induced recruitment of PKCζ and MMP-9 to podosomes.
abstract: Podosomes are adhesive structures on the ventral surface of cells that invade and degrade the extracellular matrix. Recently, we reported that phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator, induced podosome formation in normal human bronchial epithelial (NHBE) cells, and atypical PKCζ regulated MMP-9 recruitment to podosomes for its release and activation. The objective of this study was to explore signaling pathways that are involved in PKC activation-induced podosome formation and matrix degradation. Herein, we found that PDBu increased phosphorylation of PI3K p85, Akt, Src, ERK1/2, and JNK. Inhibitors for PI3K, Akt, and Src suppressed PDBu-induced podosome formation and matrix degradation. In contrast, blockers for MEK/ERK or JNK did not inhibit podosome formation but reduced proteolytic activity of podosomes. Inhibition of PKCζ activity with its pseudosubstrate peptide (PS)-inhibited PDBu-induced phosphorylation of MEK/ERK and JNK. On the other hand, inhibition of MEK/ERK or JNK pathway did not affect PKCζ phosphorylation, but reduced the recruitment of PKCζ and MMP-9 to podosomes. We conclude that PKCζ may regulate MEK/ERK and JNK phosphorylation and in turn activated MEK/ERK and JNK may regulate the proteolytic activity of PDBu-induced podosomes by influencing the recruitment of PKCζ and MMP-9 to podosomes.
authors: Division of Cell and Molecular Biology, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada.
authors: Helan
authors: H
authors: Xiao
authors: Xiao-Hui
authors: XH
authors: Bai
authors: Yingchun
authors: Y
authors: Wang
authors: Hyunhee
authors: H
authors: Kim
authors: Alan S
authors: AS
authors: Mak
authors: Mingyao
authors: M
authors: Liu
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology*; D000099221:Protein Kinase C zeta
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; D020780:Matrix Metalloproteinase 9; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta