cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca(2+) homeostasis in melanoma cells.
Malignant melanoma is one of the most aggressive human neoplasms which develop from the malignant transformation of normal epithelial melanocytes and share the lineage with retinal cells. cGMP-phosphodiesterase 6 (PDE6) is one of the cancer-retina antigens newly identified in melanoma cells. Normally, PDE6 hydrolyzes the photoreceptor second messenger cGMP allowing the visual signal transduction in photoreceptor cells. cGMP also play an important signaling role in stimulating melanogenesis in human melanocytes. Here, we present evidence that PDE6 is a key enzyme regulating the cGMP metabolism in melanoma cells. Decrease in intracellular cGMP leads to calcium accumulation in melanoma cells. In these cells, cGMP-phosphodiesterase 6 can be activated by another cancer-retina antigen, transducin, through Wnt5a-Frizzled-2 cascade, which leads to a lowering of cGMP and an increase in intracellular calcium mobilization. Thus, the aberrant expression of PDE6 may control cGMP metabolism and calcium homeostasis in melanoma cells.
Bazhin
Alexandr V
AV
Skin Cancer Unit, German Cancer Research Center, 69120, Heidelberg, Germany. a.bazhin@dkfz.de
Tambor
Vojtech
V
Dikov
Boyan
B
Philippov
Pavel P
PP
Schadendorf
Dirk
D
Eichmüller
Stefan B
SB
D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D015293:Transducin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071818:Wnt-5a Protein
C489742:FZD2 protein, human; D051157:Frizzled Receptors; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D015293:Transducin; D006152:Cyclic GMP; D002118:Calcium