Regulation of tumor invasion and metastasis in protein kinase C epsilon-transformed NIH3T3 fibroblasts.
Protein kinase C epsilon is an oncogenic, actin nucleating protein that coordinately regulates changes in cell growth and shape. Cells constitutively expressing PKCepsilon spontaneously acquire a polarized morphology and extend long cellular membrane protrusions. Here we report that the regulatory C1 domain of PKCepsilon contains an actin binding site that is essential for the formation of elongate invadopodial-like structures, increased pericellular metalloproteinase activity, in vitro invasion of a Matrigel barrier, and the invasion and metastasis of tumors grown in vivo by PKCepsilon-transformed NIH3T3 fibroblasts in nude mice. While removing this small actin binding motif caused a dramatic reversion of tumor invasion, the deletion mutant of PKCepsilon remained oncogenic and tumorigenic in this experimental system. We propose that PKCepsilon directly interacts with actin to stimulate polymerization and the extension of membrane protrusions that transformed NIH3T3 cells use in vivo to penetrate and degrade surrounding tissue boundaries.
Tachado
Souvenir D
SD
Department of Anatomy and Cell Biology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
Mayhew
Mark W
MW
Wescott
Ginger G
GG
Foreman
Tonia L
TL
Goodwin
Crystal D
CD
McJilton
Meagan A
MA
Terrian
David M
DM
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000503:physiopathology*; D011493:Protein Kinase C / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014410:Tumor Stem Cell Assay
D000199:Actins; D007527:Isoenzymes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020780:Matrix Metalloproteinase 9