Abstract

Dr. Li Baojie, , Principal Investigator, Institute of Molecular and Cell Biology, Singapore.



Bone morphogenetic proteins (BMPs) are members of the TGF-b superfamily.  Engaging BMPs to cell surface receptors activates the canonical BMPR-Smad1/5/8 pathway and the non-canonical MAPK pathway.  BMP signaling regulates cell proliferation, differentiation, migration and apoptosis, and controls embryo development and postnatal tissue homoeostasis. Human genetic studies reveal that dysfunction of BMP-Smad signaling causes skeletal defects and juvenile polyposis.  DNA damage activates Atm/Atr, which further activates c-Abl, Chk1/2, and p53 to promote apoptosis, cell cycle arrest, and DNA repair.  This DNA damage response pathway acts as an anti-cancer barrier.  Our recent studies on knockout mouse models discovered that several proteins of the DNA damage response pathway, Atm, c-Abl and p53, play important roles in bone tissue homeostasis.  Mice deficient for Atm or c-Abl show osteoporosis, whereas mice deficient for p53 show osteosclerosis.  These proteins appear to regulate osteoblast differentiation through controlling the expression of osterix, an osteoblast specific transcription factor, via the BMP signaling pathways. Further studies established a crosstalk between the Atm-cAbl-p53 pathway and the BMP-Smad pathway, in the context of bone homeostasis and DNA damage response/oncogenesis.  Finally, mouse genetic studies also revealed that BMP pathways can be regulated by protein palmitoylation, a reversible modification carried out by a zf-DHHC domain containing protein Aph2, which was identified as a c-Abl interacting protein and deficiency of which causes congenital heart defects in mouse. These findings suggest that BMP signaling pathways play a central role in bone homeostasis and tumorigenesis and that BMPs can be potential targets for osteoporosis and cancer therapy.