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E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.

ABSTRACT: E-cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion-dependent regulation of signaling has not been elucidated. We report that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand-dependent activation in association with decreases in receptor mobility and in ligand-binding affinity. E-cadherin did not regulate a constitutively active mutant RTK (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two classes of G protein-coupled receptors. EGFR regulation by E-cadherin was associated with complex formation between EGFR and E-cadherin that depended on the extracellular domain of E-cadherin but was independent of beta-catenin binding or p120-catenin binding. Transfection of E-cadherin conferred negative RTK regulation to human melanoma and breast cancer lines with downregulated endogenous E-cadherin. Abrogation of E-cadherin regulation may contribute to the frequent ligand-dependent activation of RTK in tumors.

SUBMITTER: Qian X

PROVIDER: S-EPMC394229 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.

Qian Xiaolan X Karpova Tatiana T Sheppard Allan M AM McNally James J Lowy Douglas R DR

The EMBO journal 20040401 8

E-cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion-dependent regulation of signaling has not been elucidated. We report that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand-dependent activation in association with decreases in receptor mobility and in ligand-binding affinity. E-cadherin did ...[more]

PMID: 15057284

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Project description:CD148 is a transmembrane tyrosine phosphatase that is expressed at cell junctions. Recent studies have shown that CD148 associates with the cadherin/catenin complex and p120 catenin (p120) may serve as a substrate. However, the role of CD148 in cadherin cell-cell adhesion remains unknown. Therefore, here we addressed this issue using a series of stable cells and cell-based assays. Wild-type (WT) and catalytically inactive (CS) CD148 were introduced to A431D (lacking classical cadherins), A431D/E-cadherin WT (expressing wild-type E-cadherin), and A431D/E-cadherin 764AAA (expressing p120-uncoupled E-cadherin mutant) cells. The effects of CD148 in cadherin adhesion were assessed by Ca2+ switch and cell aggregation assays. Phosphorylation of E-cadherin/catenin complex and Rho family GTPase activities were also examined. Although CD148 introduction did not alter the expression levels and complex formation of E-cadherin, p120, and β-catenin, CD148 WT, but not CS, promoted cadherin contacts and strengthened cell-cell adhesion in A431D/E-cadherin WT cells. This effect was accompanied by an increase in Rac1, but not RhoA and Cdc42, activity and largely diminished by Rac1 inhibition. Further, we demonstrate that CD148 reduces the tyrosine phosphorylation of p120 and β-catenin; causes the dephosphorylation of Y529 suppressive tyrosine residue in Src, a well-known CD148 site, increasing Src activity and enhancing the phosphorylation of Y228 (a Src kinase site) in p120, in E-cadherin contacts. Consistent with these findings, CD148 dephosphorylated both p120 and β-catenin in vitro. The shRNA-mediated CD148 knockdown in A431 cells showed opposite effects. CD148 showed no effects in A431D and A431D/E-cadherin 764AAA cells. In aggregate, these findings provide the first evidence that CD148 promotes E-cadherin adhesion by regulating Rac1 activity concomitant with modulation of p120, β-catenin, and Src tyrosine phosphorylation. This effect requires E-cadherin and p120 association.

Project description:Chlamydiae are well known for their species specificity and tissue tropism, and yet the individual species and strains show remarkable genomic synteny and share an intracellular developmental cycle unique in the microbial world. Only a relatively few chlamydial genes have been linked to specific disease or tissue tropism. Here we show that chlamydial species associated with human infections, Chlamydia trachomatis and C. pneumoniae, exhibit unique requirements for Src-family kinases throughout their developmental cycle. Utilization of Src-family kinases by C. trachomatis includes tyrosine phosphorylation of the secreted effector Tarp during the entry process, a functional role in microtubule-dependent trafficking to the microtubule organizing center, and a requirement for Src-family kinases for successful initiation of development. Nonhuman chlamydial species C. caviae and C. muridarum show none of these requirements and, instead, appear to be growth restricted by the activities of Src-family kinases. Depletion of Src-family kinases triggers a more rapid development of C. caviae with up to an 800% increase in infectious progeny production. Collectively, the results suggest that human chlamydial species have evolved requirements for tyrosine phosphorylation by Src-family kinases that are not seen in other chlamydial species. The requirement for Src-family kinases thus represents a fundamental distinction between chlamydial species that would not be readily apparent in genomic comparisons and may provide insights into chlamydial disease association and species specificity. Chlamydiae are well known for their species specificity and tissue tropism as well as their association with unique diseases. A paradox in the field relates to the remarkable genomic synteny shown among chlamydiae and the very few chlamydial genes linked to specific diseases. We have found that different chlamydial species exhibit unique requirements for Src-family kinases. These differing requirements for Src-family kinases would not be apparent in genomic comparisons and appear to be a previously unrecognized distinction that may provide insights to guide research in chlamydial pathogenesis.

Dataset Information

E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.

Publications

E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.

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