Specific inhibition of FGF-induced MAPK activation by the receptor-like protein tyrosine phosphatase LAR

Abstract

LAR is a widely expressed receptor-like protein tyrosine phosphatase that is implicated in regulation of intracellular signaling triggered by both cell adhesion and peptide growth factors. Genetic studies revealed that LAR regulates neuron axon path ®nding in Drosophila and mammary gland epithelial cell dierentiation in mice. The molecular mechanism underlying the tissue speci®c function of LAR has not been clearly understood. We investigated the role and mechanism of LAR in peptide growth factors EGF and FGF signaling in human tissue culture cells in which the expression of LAR is under the control of an inducible promoter. We found that although both EGF and FGF induce activation of mitogen-activated protein kinase (MAPK), LAR only inhibits FGF-induced MAPK activation. LAR does not interact directly with the peptide growth factor receptors, since the ligand-induced autophosphorylation of growth factor receptors was not aected by induction of LAR. The speci®c eect of LAR on FGF-induced MAPK activation appeared to be mediated by speci®c inhibition of the phosphorylation of two signal transducers that act downstream of the FGF receptor, FRS2 and a 180 kDa protein, and by prevention of their interaction with the adaptor protein GRB2. In contrast, LAR selectively inhibited the epidermal growth factor (EGF)-induced phosphorylation of p130 CAS and the formation of the complex between p130 CAS and GRB2 but this eect did not in¯uence the activation of MAPK by EGF. These data suggest that LAR and similar receptor-like protein tyrosine phosphatases may contribute to the regulation of transmembrane signaling by selectively inhibiting the tyrosine phosphorylation of speci®c signal transducers that act downstream of the plasma membrane-associated tyrosine kinases. The consequent inhibition of the formation of signaling complexes by these proteins may contribute to the speci®city of the signals generated by speci®c peptide growth factors as well as extracellular matrix proteins.

Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor

“…LAR is a widely expressed receptorlike protein tyrosine phosphatase that is implicated in regulation of intracellular signaling triggered by both cell adhesion and peptide growth factors (Serra-Pages et al, 1995). Wang et al (2000) indicated that LAR can inhibit FGF-induced MAPK activation by inhibiting the tyrosine phosphorylation of signal transducers that act downstream of the FGF receptor and the overexpression of LAR in mammalian cells induces caspase-dependent apoptosis (Weng et al, 1999).…”

Targets of Fibroblast Growth Factor 1 (FGF-1) and FGF-2 Signaling Involved in the Invasive and Tumorigenic Behavior of Carcinoma Cells

“…Thus, we hypothesized that in autocrine carcinoma cells, the LAR-PTP protein level and subsequent activity is not sufficient enough to counterbalance the kinase activity resulting from the FGFR signaling. On the basis of this hypothesis, we looked at the status of FRS2, a substrate of LAR-PTP involved in the FGFR signaling (Wang et al, 2000). The level of FRS2 expression by parental cells and FGF producing NBT-II cells was similar (Figure 5Aa), indicating that the FGFR level neither affects nor modulates the FRS2 expression; however, FRS2 was strongly tyrosine phosphorylated in cells that are autocrine for FGF-2 (Figure 5Ab).…”

“…LAR-PTP may dephosphorylate ␤-catenin, thereby favoring its interaction with E-cadherin and the maintenance of adherens junctions at the plasma membrane (Muller et al, 1999). LAR-PTP is also implicated in the regulation of FGF/FGFR signaling as it interacts with and dephosphorylates FRS2, a FGFR docking protein, resulting in the blockade of downstream signaling via pathways such as the MAPKs and PI3K pathways (Wang et al, 2000).…”

“…LAR-PTP also interacts with activated phosphorylated FRS2. Wang et al (2000) have demonstrated that such an interaction is transient and may depend on the expression level of the FGFR. In NBT-II cells overexpressing the FGFR1, LAR-PTP is significantly expressed and can be coimmunoprecipitated together with FRS2 by an anti-FRS2 antibody.…”

“…In NBT-II carcinoma cells, it has been demonstrated that upon EGF-induced cell dissociation, ␤-catenin is rapidly dephosphorylated by LAR-PTP (Muller et al, 1999). Increased or suppressed LAR-PTP expression is associated with a strong modulation of the tyrosine phosphorylation of tyrosine kinase receptors and of downstream signaling molecules such as fibroblast growth factor receptor substrate 2 (FRS2) and insulin receptor substrate 1 (IRS1), the docking proteins of FGFR and IGFR, respectively (Kulas et al, 1996;Weng et al, 1998;Wang et al, 2000).…”