Abstract
Low molecular weight protein tyrosine phosphatase (LMW-PTP) has been associated with cell proliferation control through dephosphorylation and inactivation of growth factor receptors such as PDGF-R and EphA2, and with cellular adhesion and migration through p190RhoGap and RhoA. We aim to clarify the role of two main LMW-PTP isoforms in breast cancer tumorigenesis. We used a siRNA-mediated loss-of-function in MDA-MB-435 breast cancer cell line to study the role of the two main LMW-PTP isoforms, fast and slow, in breast cancer tumorigenesis and migration. Our results show that the siRNAs directed against total LMW-PTP and LMW-PTP slow isoform enhanced cell motility in an invasive breast cancer cell line, MDA-MB-435, with no changes in the proliferation and invasive potential of cells. The total LMW-PTP knockdown caused a more pronounced increase of cell migration. Suppression of total LMW-PTP decreased RhoA activation and suppression of the LMW-PTP slow isoform caused a small but significant increase in RhoA activation. We propose that the increase or decrease in RhoA activation induces changes in stress fibers formation and consequently alter the adhesive and migratory potential of cells. These findings suggest that the two main isoforms of LMW-PTP may act differentially, with the fast isoform having a more prominent role in tumor cell migration. In addition, our results highlight functional specificity among LMW-PTP isoforms, suggesting hitherto unknown roles for these proteins in breast cancer biology. Novel therapeutic approaches targeting LMW-PTP, considering the expression of these two isoforms and not LMW-PTP as a whole, should be investigated.
Highlights
Protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) regulate the reversible phosphorylation of tyrosine residues in proteins, controlling vital physiological processes [1].In humans, class II cysteine-based PTPs are represented by members of the Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) family, which are widely expressed, with no particular tissue specificity
Our results show that blocking total LMW-PTP and its slow isoform by siRNA in the MDA-MB-435 cell line, a breast cancer invasive cell line, results in increased migratory potential, which our results suggest to occur through RhoA
Knockdown of total LMW-PTP and the two LMW-PTP isoforms was achieved in 3 clones (CII, CIII and CV) and clone CIV was a specific knockdown of the slow isoform
Summary
Class II cysteine-based PTPs are represented by members of the Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) family, which are widely expressed, with no particular tissue specificity. The enzyme has two main isoforms, IF1 (fast) and IF2 (slow), both small enzymes consisting of only 157 amino acid residues and with a molecular weight of 18kDa. The amino acid sequence shows that the two isoforms arise from alternative and mutually exclusive splicing of exon 3 or 4 [2]. LMW-PTP has been largely considered a negative regulator of growth factor-induced cell proliferation, in some instances it acts as a positive regulator. Some proteins, such as Ephrin Receptor A2 (EphA2), seem to be involved in the regulation of carcinogenesis by LMW-PTP. It is known that LMW-PTP has the potential to dephosphorylate EphA2
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