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    MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice.

    Mutations in human FYVE, RhoGEF, and PH domain–containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome). FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown.  The authors describe a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). They found that MLK3 is downstream of FGD1 and regulates ERK and p38 MAPK, which in turn phosphorylate and activate Runx2 to influence osteoblast differentiation.


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