Abstract
A novel function for the binder of Arl two (BART) molecule in pancreatic cancer cells is reported. BART inhibits invasiveness of pancreatic cancer cells through binding to a Ca2+-dependent, phosphorylated, guanosine triphosphatase (GTPase) membrane fusion protein, annexin7 (ANX7). A tumor suppressor function for ANX7 was previously reported based on its prognostic role in human cancers and the cancer-prone mouse phenotype ANX7(+/−). Further investigation demonstrated that the BART–ANX7 complex is transported toward cell protrusions in migrating cells when BART supports the binding of ANX7 to the protein kinase C (PKC) isoform PKCα. Recent evidence has suggested that phosphorylation of ANX7 by PKC significantly potentiates ANX7-induced fusion of phospholipid vesicles; however, the current data suggest that the BART–ANX7 complex reduces PKCα activity. Knocking down endogenous BART and ANX7 increases activity of PKCα, and specific inhibitors of PKCα significantly abrogate invasiveness induced by BART and ANX7 knockdown. These results imply that BART contributes to regulating PKCα activity through binding to ANX7, thereby affecting the invasiveness of pancreatic cancer cells. Thus, it is possible that BART and ANX7 can distinctly regulate the downstream signaling of PKCα that is potentially relevant to cell invasion by acting as anti-invasive molecules.
Highlights
The binder of Arl two (BART) molecule is a soluble 19-kDa protein originally purified from bovine brain and identified as a binding partner of ADP-ribosylation factor-like 2 (ARL2) [1]
Depletion of BART did not induce accumulation of ANX7 at the leading edges and subsequent colocalization with phosphorylated PKCa. These results indicate that PKCa is interdependently associated with BART and ANX7 in modulating pancreatic ductal adenocarcinoma (PDAC) cell migration
(iii) Phosphorylated PKCa is responsible for the increased invasiveness of PDAC cells seen with BART or ANX7 knockdown
Summary
The binder of Arl two (BART) molecule is a soluble 19-kDa protein originally purified from bovine brain and identified as a binding partner of ADP-ribosylation factor-like 2 (ARL2) [1]. We previously reported that regulation of BART post-transcriptional modification via intracellular CD24 binding to G3BP in stress granules contributes to inhibition of invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC) cells [4]. Further study demonstrated that BART decreases invasiveness of PDAC cells by inhibiting the ARL2-mediated decrease in the activity of the Rho GTPase protein RhoA [6]. These data suggest that BART plays a role in inhibition of PDAC invasiveness
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
