A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival

Abstract

During chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-β type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response.

A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling

“…This suggests that MET inhibiting ZNRF3 may not only upregulate canonical Wnt signalling but also cross-talk with other FZD-dependent pathways such as Wnt/STOP (Taelman et al 2010;Acebron et al 2014), Wnt/PCP, and Wnt/Ca2+ (Miller et al 1999;Hao et al 2012;Tsukiyama et al 2015), as well as BMPR1A-BMP4 signalling. The reported HGF-induced hyperactivation of BMP-SMAD signalling would be consistent with this possibility (Addante et al 2020).…”

BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma

“…Bone morphogenetic protein 9 (BMP9), a member of the BMP subgroup of the TGF-β superfamily proteins that signal via type I and type II BMP receptors, is involved osteogenesis, angiogenesis and liver development [18,9]. BMP9 has recently been reported to be associated with liver diseases including cancer [19,16]. However, unlike TGF-β, which has been reported to be associated with HCC-CSCs [20][21][22], the relationship between BMPs and HCC-CSCs has been unclear.…”

“…The malignant nature of HCC is now thought to be associated with the presence of CSCs, and therefore, the development of therapeutic options against CSCs is strongly desired. Bone morphogenetic protein 9 (BMP9), a member of the BMP subgroup of the TGFb superfamily proteins that signal via type I and type II BMP receptors, is involved in osteogenesis, angiogenesis, and liver development [8,17]. BMP9 has recently been reported to be associated with liver diseases including cancer [15,18].…”

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…In HepG2 cells, BMP9 activates Akt and p38 pathways inducing proliferative responses [108]. It has also been described that BMP9 induces the activation of p38 in oval cells, promoting cell death [109]. In glioblastoma cell lines, BMP9 activates PI3K, p38, Akt and Erk1/2 to promote invasiveness [105].…”