Biomedical Engineering Reference
In-Depth Information
Finally, phosphorylation appears to be an important regulatory mecha-
nism for Vangl protein function. Early work by Kalabis, Rosenberg, and
Podolsky (2006) showed that Vangl1 is phosphorylated in response to intes-
tinal trefoil factor (ITF)/TFF3, which reduces Vangl1 plasma membrane
localization and may affect cell motility. More recently, Gao et al. (2011)
observed that Vangl2 interacts with Ror2 and is phosphorylated both in vivo
and in vitro . In addition, Vangl2 phosphorylation is stimulated by Wnt
ligands. A Ser/Thr cluster at Vangl2 amino terminus is targeted for phos-
phorylation, and the importance of this event is revealed by the presence
of hVANGL1 (S83L) and hVANGL2 (S84F) variants at this site in human
NTD patients. Finally, coexpression of Lp -associated variant Vangl2 S464N
reduced phosphorylation of the WT protein expressed in the same cell.
These results have provided a model in which Vangl2 phosphorylation
and associated role in PCP are regulated by Wnt ligands ( Gao et al., 2011 ).
5. CONCLUSIONS
The pivotal role of Vangl2 in NT formation was originally established
10 years ago with the discovery that mutations in Vangl2 are responsible for
the severe NTD craniorachischisis in the well-known mouse mutant Loop-tail
( Kibar, Vogan, et al., 2001 ). The careful examination of morphology and
dynamic developmental processes altered in Lp mice have revealed that Vangl2
plays a similarly important role in patterning and development of a many tissues
and organs. The genetic interaction studies inmice heterozygous for Vangl2 Lp/ þ
and for mutations in other genes have linked Vangl2 and the uniquely Vangl2-
sensitivePCPpathway to a number of additional andunsuspectedphenomena
such as asymmetric cell division, cell migration, and function of key cellular
appendages such as cilia. With such a rich spectrum of biological activities es-
sential for normal embryonic development, it is tempting to speculate that
Vangl2 also plays an important role in the structural integrity and functional
homeostasis of adult organs, tissues, and cells. The recent generation of con-
ditional mutant alleles at Vangl2 enabling tissue and temporal-specific genetic
ablation of Vangl2 will likely be very informative and may also point at the
possible association of Vangl2 with the diseases of adult tissues.
ACKNOWLEDGMENTS
E. T. and P. G. are supported by grants from the Canadian Institute of Health Research. E. T.
is a recipient of the Fonds de Recherche en Sant ´ du Quebec award, and P. G. is a James
professor, McGill University.
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