Abstract
Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3, DU145, and BPH1 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80, but not AMOT p130, functioned as a tumor promoter by enhancing PCa cell proliferation. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.
Highlights
Angiomotin (AMOT) is a family of proteins originally identified as an angiostatin binding protein that regulates endothelial cell migration and tube formation [1, 2]
We showed that one of the mechanisms of AMOTp80-mediated proliferation is through inhibition of the Hippo pathway, resulting in nuclear translocation of YAP and an increased expression of the YAP target gene bone morphogenetic protein 4 (BMP4)
We further showed that AMOTp80-mediated BMP4 expression promotes prostate cancer (PCa) cell proliferation
Summary
Angiomotin (AMOT) is a family of proteins originally identified as an angiostatin binding protein that regulates endothelial cell migration and tube formation [1, 2]. AMOT was recently found to play important roles in neurofibromatosis type 2 (NF2), breast cancer, and renal cell carcinoma [5,6,7]. AMOT could interact with the cell junction protein RICH1, and this interaction leads to the localization of AMOT to the apical membrane of polarized epithelial cells [3, 4]. AMOT was proposed to coordinate www.impactjournals.com/oncotarget the dysregulation of cell polarity with the induction of neoplastic growth [6]. AMOT was shown to regulate endothelial cell migration and tube formation [1, 2]. AMOT-mediated cell migration was critical in embryogenesis as knockout of AMOT in zebrafish and in mouse led to embryonic lethality due to defects in cell migration into proximal extra-embryonic regions [8, 9]
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