FzRs as GPCRs

Although the FzRs exhibit several hallmarks of GPCRs, including presumed heptahelical structures, and exhibit Pertussis toxin- and specific G protein Ga or Gpg subunit-dependent signaling, their G protein activation capabilities have been investigated only minimally, and the FzRs are often still regarded as new members of the GPCR superfamily.112 Some FzRs have been shown to activate hetero-trimeric guanine nucleotide-binding (G) proteins.112122 The receptors appear to couple to members of the Gi/o family of G proteins to activate PLCp (via het-erodimeric Gpg subunits),115 resulting in increased concentrations of intracellular calcium (Ca2+). They also appear to activate phosphodiesterases (PDEs)114 through

Gatransducin 2 (Gt2) to lower intracellular concentrations of cyclic guanosine monophosphate (cGMP).

Numerous reports discuss the involvement of altered expression levels of both Wnts and FzRs in cancers. For instance, an upregulation of Frizzled-7 (FZD7) has been reported in human gastric cancer,123 and upregulation in the expression of Wnt5a in carcinomas of the lung, breast, prostate, and melanomas has been docu-mented.124 Moreover, melanoma cells with both low Wnt5a expression and low in vitro invasion show increased invasiveness in vitro upon transfection with exogenous

Wnt5a, while treatment of the cells with an antibody to Frizzled-5 inhibited the binding of Wnt5a to the receptor and resulted in decreased invasiveness.125

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