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Abstract
The frizzled gene family of putative Wnt receptors encodes proteins that have a seven transmembrane-spanning motif characteristic of G-protein-linked receptors, although no loss-of-function studies have demonstrated a requirement for G-proteins for Wnt signaling by the gene product of frizzled-1. Medium conditioned by mouse F9 teratocarcinoma stem cells stably transfected to express either Xenopus Wnt-5a or Wnt-8 was used to test primitive endoderm formation of F9 stem cells. F9 stem cells expressing the rat Frizzled-1 receptors demonstrated endoderm formation in response to conditioned medium containing Wnt-8 but not to medium containing Wnt-5a. Primitive endoderm formation stimulated by Wnt-8 acting on the rat Frizzled-1 receptor was blocked by treatment with pertussis toxin by depletion of either Galpha(o) or Galpha(q) via antisense oligodeoxynucleotides, as well as by inhibitors of protein kinase C (bisindoylmaleimide) and of mitogen-activated protein kinase kinase (PD98059). Our results demonstrate the requirement for G-protein subunits Galpha(o) (a pertussis toxin substrate) and Galpha(q) for signaling by Frizzled-1, and an obligate role for the protein kinase C (likely mediated through stimulation of Galpha(q)) and mitogen-activated protein kinase network at the level of mitogen-activated protein kinase kinase.
Highlights
Wnts are a class of vertebrate genes encoding secreted signaling proteins, which appear to modulate diverse processes in developing vertebrate embryos and in some adult tissues [1,2,3,4]
Our results demonstrate the requirement for G-protein subunits G␣o and G␣q for signaling by Frizzled-1, and an obligate role for the protein kinase C and mitogen-activated protein kinase network at the level of mitogen-activated protein kinase kinase
Several lines of evidence suggest that one frizzled gene product (Frizzled-2) is a member of the superfamily of G-proteinlinked receptors, including: a proposed heptihelical structural motif typical of G-protein-linked receptors [39]; sensitivity to the inhibitory action of pertussis toxin, a cardinal property of signaling via a heterotrimeric G-protein of the Gt, Gi, and Go family [6]; sensitivity to expression of G-protein ␣-subunits that reduce the level of uncomplexed, “free” /␥-subunits; and coupling to effectors often associated with G-protein mediation [40]
Summary
Wnts are a class of vertebrate genes encoding secreted signaling proteins, which appear to modulate diverse processes in developing vertebrate embryos and in some adult tissues [1,2,3,4]. Primitive endoderm formation stimulated by Wnt-8 acting on the rat Frizzled-1 receptor was blocked by treatment with pertussis toxin by depletion of either G␣o or G␣q via antisense oligodeoxynucleotides, as well as by inhibitors of protein kinase C (bisindoylmaleimide) and of mitogen-activated protein kinase kinase (PD98059).
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