Noncanonical Wnt Signaling through G Protein-Linked PKC

Activation Promotes Bone Formation

Xiaolin et al. Dev cell. (2007)

Christine Hartmann. Trends cell biol. (2006)

Formation of the skeleton through intramembranous and endochondral ossification

Intramembranousossification

Endochondralossification

Christine Hartmann. Trends cell biol. (2006)

Role of canonical Wnt--cat signaling during lineage differentiation and maturation of osteoblasts

Skeletal defects caused by mutations with regard to components of the canonical Wnt pathway

Christine Hartmann. Trends cell biol. (2006)

Malbon CC. Nat Rev Mol Cell Biol . 2005.

Rhee SG. Annu Rev Biochem. 2001.

G-protein signaling and PLC mediated PKC activation

Classic PKC (cPKC) : , 1, 2,

→ activated by DAG,

phosphatidylserine and Ca2+

Novel PKC (nPKC) : , , ,

→ activated by DAG and

phosphatidylserine

Atypical PKC (aPKC) : , ,

→ activated by phosphatidylserine

Sheldahl et al. Curr Biol. (1999) Sheldahl et al. J Cell Biol. (2003)

Wnts activate PKC through G-protein signal

Penzo-Mendez et al. Dev Biol. (2003)

Wnt3a induces osteoblast differentiation and MARCKS phosphorylation via PKCin ST2 cells

Wnt3a nPKC

osteoblastogenesis

PKC Is Required for Wnt3a-Induced Osteoblastogenesis, but Not for Canonical Wnt Signaling in ST2 Cells

PKC cPKC Ca2+ nPKC()

aPKC : PKC pseudosubstrate PKC pseudosubstrate

Rottlerin Inhibits Wnt3a-Induced Osteoblast Differentiation in ST2 Cells

Wnt3a

PKC

osteoblastogenesis -cat

PKC Activation via Gq Signaling Promotes Wnt3a-Induced Osteoblastogenesis and Requires Dvl in ST2 Cells

Pertussis toxin: Gi-G inhibitor

Gq family : Gq, G11, G14/15/16

Wnt3a

PKC

osteoblastogenesis

-cat

DvlGq

PLC

PKC Activation by Wnt3a Correlates with Dvl-2 Translocation to the Plasma Membrane and Is Insensitive to Dkk1 in ST2Cells

Wnt3a Induces Colocalization of PKCδ and Dvl-1,3 at the Plasma Membrane in ST2 Cells

Removal of PKC Results in a Deficit in Embryonic Bone Formation

Wnt7b Induces Osteoblastogenesis and PKC Activity, but Does Not Activate Canonical Wnt Signaling

Removal of Wnt7b in Skeletal Cells Results in Defects in Bone Formation

αβ

LRP

γ

Wnt

Dvl

FZ

PLC

PKC

??

Osteoblastogenesis

-cat

Model for Wnt-PKC signaling promotes bone formation