Abstract
The metastasis-associated tyrosine phosphatase PRL-3/PTP4A is upregulated in numerous cancers, but the mechanisms modulating PRL-3 activity other than its expression levels have not been investigated. Here we report evidence for both Src-dependent tyrosine phosphorylation of PRL-3 and Src-mediated regulation of PRL-3 biological activities. We used structural mutants, pharmacological inhibitors and siRNA to demonstrate Src-dependent phosphorylation of endogenous PRL-3 in SW480 colon cancer cells. We also demonstrated that PRL-3 was not tyrosine phosphorylated in SYF mouse embryo fibroblasts deficient in Src, Yes and Fyn unless Src was re-expressed. Further, we show that platelet-derived growth factor (PDGF) can stimulate PRL-3 phosphorylation in a Src-dependent manner. Finally, we show that PRL-3-induced cell motility, Matrigel invasion and activation of the cytoskeleton-regulating small GTPase RhoC were abrogated in the presence of the phosphodeficient PRL-3 mutant Y53F, or by use of a Src inhibitor. Thus, PRL-3 requires the activity of a Src kinase, likely Src itself, to promote these cancer-associated phenotypes. Our data establish a model for the regulation of PRL-3 by Src that supports the possibility of their coordinate roles in signaling pathways promoting invasion and metastasis, and supports simultaneous use of novel molecularly targeted therapeutics directed at these proteins.
Highlights
Extensive evidence has accumulated linking the putative tyrosine phosphatase PRL-3 with invasion and metastasis
PRL-3 is phosphoryated in vitro by the Src tyrosine kinase, and endogenous PRL-3 is tyrosinephosphorylated in cells
The tyrosine phosphatase PRL-1, which shares all six tyrosine residues in common with its close relative, PRL-3, has been shown to be phosphorylated in vitro by the tyrosine kinase Src [25], the study did not determine the site of phosphorylation or whether it occurs in vivo
Summary
Extensive evidence has accumulated linking the putative tyrosine phosphatase PRL-3 with invasion and metastasis (reviewed in [1,2,3]). One possible mechanism of regulation other than expression levels is posttranslational modification of PRL-3, such as phosphorylation In support of this possibility, there is evidence for the regulation of tyrosine phosphatases downstream of tyrosine kinases, including the proto-oncogene Src. For example, low molecular weight protein tyrosine phosphatase (LMW-PTP) is phosphorylated by Src [14], as well as by Fyn and Lck [15], and the EphA8 receptor tyrosine kinase [16]. Low molecular weight protein tyrosine phosphatase (LMW-PTP) is phosphorylated by Src [14], as well as by Fyn and Lck [15], and the EphA8 receptor tyrosine kinase [16] This modification affects both the catalytic activity of LMW-PTP [16,17,18] and its association with the adapter protein Grb2 [17]. PRL-1, which shares all six tyrosines in common with PRL-3, was shown to be phosphorylated by Src in vitro [25], suggesting that PRL phosphatases may be regulated by Src family kinases
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