Liprin β1, a Member of the Family of LAR Transmembrane Tyrosine Phosphatase-interacting Proteins, Is a New Target for the Metastasis-associated Protein S100A4 (Mts1)

Abstract

Metastasis-associated protein S100A4 (Mts1) induces invasiveness of primary tumors and promotes metastasis. S100A4 belongs to the family of small calcium-binding S100 proteins that are involved in different cellular processes as transducers of calcium signal. S100A4 modulates properties of tumor cells via interaction with its intracellular targets, heavy chain of non-muscle myosin and p53. Here we report identification of a new molecular target of the S100A4 protein, liprin ␤1. Liprin ␤1 belongs to the family of leukocyte common antigen-related (LAR) transmembrane tyrosine phosphatase-interacting proteins that may regulate LAR protein properties via interaction with another member of the family, liprin ␣1. We showed by the immunoprecipitation analysis that S100A4 interacts specifically with liprin ␤1 in vivo. Immunofluorescence staining demonstrated the co-localization of S100A4 and liprin ␤1 in the cytoplasm and particularly at the protrusion sites of the plasma membrane. We mapped the S100A4 binding site at the C terminus of the liprin ␤1 molecule between amino acid residues 938 and 1005. The S100A4-binding region contains two putative phosphorylation sites by protein kinase C and protein kinase CK2. S100A4-liprin ␤1 interaction resulted in the inhibition of liprin ␤1 phosphorylation by both kinases in vitro.Metastasis-associated protein S100A4 is highly expressed in metastatic tumors and tumor cell lines of different origins, and its expression is tightly associated with poor prognosis in cancer patients (1-6). The direct involvement of S100A4 in the formation of metastases has been shown in transgenic models, where the murine mammary tumor virus-S100A4 transgene provoked malignant progression of mammary tumors in mice (7,8).Different attempts have been made to elucidate the mechanisms underlying the role of S100A4 in tumor progression. Modulating the expression level of S100A4 in numerous tumor cell lines revealed its direct role in cell motility, invasiveness,

A new role for PGRP-S (Tag7) in immune defense: lymphocyte migration is induced by a chemoattractant complex of Tag7 with Mts1

“…Several glycosylation sites are known for Tag7 protein, 16 and Mts1 can be phosphorylated by PKC. 33 In addition, our results demonstrated that Mts1 in a leukocyte conditioned medium can be in 2 alternative forms, monomeric and tetrameric, and these properties of Mts1, possibly, could affect the chemotactic activity of the Tag7-Mts1 complex. It is also worth noting that other proteins could interact with the Tag7-Mts1 complex.…”

“…Proteins were visualized using ECL Plus detection reagents (GE Healthcare) according to the manufacturer's protocol. The contents of Mts1 33 and Tag7 20 in samples were measured by a ELISA.…”

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

“…[13][14][15] S100A4 also induces a migratory phenotype by affecting cell adhesion via binding to liprin ␤1. 16 Moreover, S100A4 binds to the tumor suppressor p53 and modulates its transcriptional activity. 17 Extracellular S100A4 activates expression of several matrix metalloproteinases, thereby enabling cell invasion into adjacent tissues and facilitating angiogenesis.…”

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

“…The poor outlook for cancer patients with elevated expression of S100A4 is likely to be due to the ability of S100A4 to induce a metastatic phenotype; however, the mechanism of the strong metastasisinducing properties of S100A4 is not known. S100A4 has been reported to interact with a number of protein targets, at least in vitro, namely nonmuscle tropomyosin (Takenaga et al, 1994), nonmuscle myosin A heavy chain (Kriajevska et al, 1994;Ford and Zain, 1995), p53 (Grigorian et al, 2001), liprin b1 (Kriajevska et al, 2002) and methionine aminopeptidase 2 (Endo et al, 2002). S100A4 also self-associates to form a homodimer as shown by its NMR structure (Vallely et al, 2002).…”