Abstract
Uveal melanoma (UM) is an aggressive tumor in which approximately 50% of patients develop metastasis. Expression of the PTP4A3 gene, encoding a phosphatase, is predictive of poor patient survival. PTP4A3 expression in UM cells increases their migration in vitro and invasiveness in vivo. Here, we show that CRMP2 is mostly dephosphorylated on T514 in PTP4A3 expressing cells. We also demonstrate that inhibition of CRMP2 expression in UM cells expressing PTP4A3 increases their migration in vitro and invasiveness in vivo. This phenotype is accompanied by modifications of the actin microfilament network, with shortened filaments, whereas cells with a inactive mutant of the phosphatase do not show the same behavior. In addition, we showed that the cell cytoplasm becomes stiffer when CRMP2 is downregulated or PTP4A3 is expressed. Our results suggest that PTP4A3 acts upstream of CRMP2 in UM cells to enhance their migration and invasiveness and that a low level of CRMP2 in tumors is predictive of poor patient survival.
Highlights
Uveal melanoma (UM) is the most common intraocular tumor in adults
We previously showed that PTP4A3 promotes aggressiveness through membrane accumulation of matrix metalloproteinase 14 (MMP14)[15]
The densitometric profiles of CRMP2 (Fig. 1B) show that the number of CRMP2 phosphorylated spots were reduced in the presence of wildtype PTP4A3, especially those of T514, whereas there is more total phosphorylated CRMP2 in these cells (Fig. 1C), possibly due to the overexpression of SRC kinases in PTP4A3-overexpressing cells[22]
Summary
Uveal melanoma (UM) is the most common intraocular tumor in adults This tumor is very aggressive and up to 50% of patients subsequently develop distant metastasis, predominantly in the liver[1,2,3]. We showed that PTP4A3 expression in UM cells increases their migration in vitro and invasiveness in vivo[7]. Www.nature.com/scientificreports matrix (ECM), an event that is required for cell migration and invasiveness. Among PTP4A3 substates there are currently three cytoskeletal proteins that have been identified as PTP4A3 targets, providing strong evidence of PTP4A3 role promoting migration and invasion by cytoskeleton remodeling[16,17,18]. We have identified CRMP2 as a new target of PTP4A3 by 2D phosphoprotein analysis. These two proteins interact in co-immunoprecipitation assays. We found that CRMP2 is less phosphorylated on T514 after interaction with PTP4A3 in comparaison to the catalytically inactive mutant of the phosphatase, PTP4A3 (C104S)
Sign-in/Register to view highlights & summary 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.
