Isoprenylation is necessary for the full invasive potential of RhoA overexpression in human melanoma cells.
Rho GTPases are signaling molecules known to control cell motility. Several recent studies have suggested a role for Rho proteins in mediating tumor metastasis independent of their affects on cell proliferation. As Rho proteins require post-translational modification with a geranlygeranyl moiety for full activity, we tested the affect of blocking geranylation on localization, downstream signaling, and stimulation of invasion. Expression of a constitutively active Rho construct in A375 melanoma cells dramatically stimulated invasion through Matrigel membranes; however, a constitutively active RhoA mutated so that it cannot be geranylated, failed to stimulate invasion. Moreover, expression of epitope or GFP tagged modifications of this nongeranylatable constitutively active Rho demonstrated that geranylation is necessary for correct cellular localization of Rho. Geranylation was also found to be necessary for full downstream activation of serum response factor mediated transcription. Pharmacologic inhibition of Rho geranylation produced similar inhibition of Rho localization, signaling, and invasion. Our results suggest that inhibition of Rho geranylation may be an attractive pharmacologic target for inhibiting melanoma metastasis.
Collisson
Eric A
EA
Department of Medicine, Division of Dermatology, UCLA School of Medicine, Los Angeles, CA, USA.
Carranza
Dafnis C
DC
Chen
Ingrid Y
IY
Kolodney
Michael S
MS
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D001672:Biocompatible Materials; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003094:Collagen; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D008545:Melanoma; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012878:Skin Neoplasms; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
D000924:Anticholesteremic Agents; D001672:Biocompatible Materials; D004338:Drug Combinations; D006538:Heptanoic Acids; D007797:Laminin; D011509:Proteoglycans; D011758:Pyrroles; C059485:matrigel; D003094:Collagen; D000069059:Atorvastatin; D020742:rhoA GTP-Binding Protein