The Mechanism Of FAM134C In BMP Signaling Pathway

BMPs (Bone morphogenetic proteins) are a subgroup of growth factors which belong to the TGF-β (Transforming growth factor-β) superfamily and play key roles in multiple physiological and pathological processes. BMP signaling not only controls bone formation, chondrogenesis, embryonic development and differentiation, but also plays a crucial role in keeping homeostasis of mature organism. Smad proteins are the intracellular mediators of TGF-β/BMP signaling pathway. There are three subgroups of Smad proteins implicated in TGF-β/BMP singling pathway:R-Smads (Receptor regulated Smads), Co-Smad (Common mediator Smad) and I-Smads (inhibitory Smads). Smadl/5/8are the functional R-Smads in BMP signaling pathway while Smad2/3are involved in TGF-β signaling. Upon BMPs stimulation, Smadl/5/8and Smad4form a protein complex and then translocate into the nucleus to mediate BMP-induced gene transcription.By using tandem affinity purification, we screened for Smad5interaction proteins and identified FAM134C (family with sequence similarity134, member C) as a potential candidate. FAM134C belongs to FAM134superfamily (family with sequence similarity134), which include FAM134A (family with sequence similarity134, member A), FAM134B (family with sequence similarity134, member B) and FAM134C. According to the NCBI database, FAM134C contains three transmembrane domains and may locate on cell membranes. We can only find two reports related to FAM134C:One reported that FAM134C is regulated by NRF-1and then enhance neurite outgrowth in neuroblastoma cells and hippocampal neurons, another one reported that the FAM134C protein level is up-regulated in S. aureus-infected susceptible (A/J) and humans with S. Aureus blood stream infection, but not in resistant (C57BL/6J) mice and healthy human subjects. However, no connections between FAM134C and BMP signaling pathway has been mentioned yet.Furthermore, we confirmed that FAM134C locates on cell plasma membrane and interacts with ALK3. More interestingly, we found that FAM134C can promote ALK3degradation in a proteasome dependent pathway, and then block downstream signaling transduction.In summary, we found that FAM134C mediates BMP signaling through the interaction with ALK3. This result enriches the understanding of BMP signaling pathway and provides the theoretical basis for coming up with a new drug target related to BMP signaling.