Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility.
The combination of an increase in the cAMP-phosphodiesterase activity of h-prune and its interaction with nm23-H1 have been shown to be key steps in the induction of cellular motility in breast cancer cells. Here we present the molecular mechanisms of this interaction. The region of the nm23-h-prune interaction lies between S120 and S125 of nm23, where missense mutants show impaired binding; this region has been highly conserved throughout evolution, and can undergo serine phosphorylation by casein kinase I. Thus, the casein kinase I delta-epsilon specific inhibitor IC261 impairs the formation of the nm23-h-prune complex, which translates 'in vitro' into inhibition of cellular motility in a breast cancer cellular model. A competitive permeable peptide containing the region for phosphorylation by casein kinase I impairs cellular motility to the same extent as IC261. The identification of these two modes of inhibition of formation of the nm23-H1-h-prune protein complex pave the way toward new challenges, including translational studies using IC261 or this competitive peptide 'in vivo' to inhibit cellular motility induced by nm23-H1-h-prune complex formation during progression of breast cancer.
Garzia
L
L
CEINGE, Centro di Ingegneria Genetica e Biotecnologie Avanzate, Naples, Italy.
D'Angelo
A
A
Amoresano
A
A
Knauer
S K
SK
Cirulli
C
C
Campanella
C
C
Stauber
R H
RH
Steegborn
C
C
Iolascon
A
A
Zollo
M
M
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000196:embryology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002465:Cell Movement; D002522:Chlorocebus aethiops; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D010766:Phosphorylation; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism
D002352:Carrier Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C411652:IC 261; D007211:Indoles; D054778:NM23 Nucleoside Diphosphate Kinases; D010446:Peptide Fragments; D010696:Phloroglucinol; C438732:PRUNE1 protein, human; D010744:Phosphoric Monoester Hydrolases; D010727:Phosphoric Diester Hydrolases