Yanagisawa, Masahiro

Localization of presynaptic components to synaptic sites is critical for hippocampal synapse formation. Cell adhesion–regulated signaling is important for synaptic development and function, but little is known about differentiation of the presynaptic compartment. In this study, we describe a pathway that promotes presynaptic development involving p120catenin (p120ctn), the cytoplasmic tyrosine kinase Fer, the protein phosphatase SHP-2, and β-catenin. Presynaptic Fer depletion prevents localization of active zone constituents and synaptic vesicles and inhibits excitatory synapse formation and synaptic transmission. Depletion of p120ctn or SHP-2 similarly disrupts synaptic vesicle localization with active SHP-2, restoring synapse formation in the absence of Fer. Fer or SHP-2 depletion results in elevated tyrosine phosphorylation of β-catenin. β-Catenin overexpression restores normal synaptic vesicle localization in the absence of Fer or SHP-2. Our results indicate that a presynaptic signaling pathway through p120ctn, Fer, SHP-2, and β-catenin promotes excitatory synapse development and function.

p120 catenin regulates the activity of the Rho family guanosine triphosphatases (including RhoA and Rac1) in an adhesion-dependent manner. Through this action, p120 promotes a sessile cellular phenotype when associated with epithelial cadherin (E-cadherin) or a motile phenotype when associated with mesenchymal cadherins. In this study, we show that p120 also exerts significant and diametrically opposing effects on tumor cell growth depending on E-cadherin expression. Endogenous p120 acts to stabilize E-cadherin complexes and to actively promote the tumor-suppressive function of E-cadherin, potently inhibiting Ras activation. Upon E-cadherin loss during tumor progression, the negative regulation of Ras is relieved; under these conditions, endogenous p120 promotes transformed cell growth both in vitro and in vivo by activating a Rac1–mitogen-activated protein kinase signaling pathway normally activated by the adhesion of cells to the extracellular matrix. These data indicate that both E-cadherin and p120 are important regulators of tumor cell growth and imply roles for both proteins in chemoresistance and targeted therapeutics.

During epithelial tumor progression, the loss of E-cadherin expression and inappropriate expression of mesenchymal cadherins coincide with increased invasiveness. Reexpression experiments have established E-cadherin as an invasion suppressor. However, the mechanism by which E-cadherin suppresses invasiveness and the role of mesenchymal cadherins are poorly understood. We show that both p120 catenin and mesenchymal cadherins are required for the invasiveness of E-cadherin–deficient cells. p120 binding promotes the up-regulation of mesenchymal cadherins and the activation of Rac1, which are essential for cell migration and invasiveness. p120 also promotes invasiveness by inhibiting RhoA activity, independently of cadherin association. Furthermore, association of endogenous p120 with E-cadherin is required for E-cadherin–mediated suppression of invasiveness and is accompanied by a reduction in mesenchymal cadherin levels. The data indicate that p120 acts as a rheostat, promoting a sessile cellular phenotype when associated with E-cadherin or a motile phenotype when associated with mesenchymal cadherins.