Scheme 3.
Schematic representation of cross-communication of non-canonical Wnt signalling pathways observed in bone cells. (a) Non-canonical Wnt signalling inhibits the RANK-RANKL signalling pathway through the inhibition of the formation of the TRAF6-TAB2-TAK1 complex by sequestering TAK1 to the Wnt-induced TAB2-TAK1-NLK complex. This complex activates NLK kinase, which inhibits the TCF/LEF protein family through phosphorylation. (b) The non-canonical Wnt signalling pathway interacts with mTOR in osteoblasts through two mechanisms. mTORC1 complex is activated through LRP6/Fzd-PI3K-AKT pathway and results in increased activity of S6 kinase 1 (S6K1) and increased protein synthesis. On the other hand, mTORC2 activation is mediated through Rho-family small GTPase RAC1 and leads to the activation of AKT and other signal transduction pathways, which results in changes in glucose and lipid energy metabolism, cell survival and cytoskeleton reorganisation. Both processes are required for adequate cell growth and proliferation. (c) The Hippo signalling pathway is activated through cell–cell attachment and cell adhesion. When active, it activates MST1/2 kinases and LATS1/2 kinases, which inhibit YAP/TAZ activity by inducing its proteosomal degradation. Non-canonical Wnt signalling through ROR2/Gα12/13 G protein/RhoA kinase inhibits YAP/TAZ inhibitor LATS1/2. This releases YAP/TAZ from degradation and enables it to translocate to the nucleus, where it forms complexes with different transcription factors, such as TEAD or β-catenin, to regulate transcription of downstream genes. YAP/TAZ also interacts with the canonical Wnt signalling pathway by blocking the degradosome function and promoting β-catenin cytoplasmic release. (d) MAPK signalling pathways involve the activation of small GTPases RAS and a cascade of sequentially activated kinases that lead to the activation of ERK1/2, JNK and p38 MAPKs. Activation of canonical Wnt signalling and inhibition of degradosome not only leads to the release of β-catenin but also stabilises RAS and thus activates the MAPK cascade. At the same time, p38 promotes Wnt/β-catenin signalling through the inhibition of the destruction complex. Not enough information is known to reliably construct the interactions of the non-canonical Wnt with MAPK signalling pathway in bone cells.