The Nonreceptor Tyrosine Kinase Fer Mediates Cross-Talk between N-Cadherin and β1-Integrins

Abstract

Cadherins and integrins must function in a coordinated manner to effectively mediate the cellular interactions essential for development. We hypothesized that exchange of proteins associated with their cytoplasmic domains may play a role in coordinating function. To test this idea, we used Trojan peptides to introduce into cells and tissues peptide sequences designed to compete for the interaction of specific effectors with the cytoplasmic domain of N-cadherin, and assayed their effect on cadherin- and integrin-mediated adhesion and neurite outgrowth. We show that a peptide mimicking the juxtamembrane (JMP) region of the cytoplasmic domain of N-cadherin results in inhibition of N-cadherin and β1-integrin function. The effect of JMP on β1-integrin function depends on the expression of N-cadherin and is independent of transcription or translation. Treatment of cells with JMP results in the release of the nonreceptor tyrosine kinase Fer from the cadherin complex and its accumulation in the integrin complex. A peptide that mimics the first coiled-coil domain of Fer prevents Fer accumulation in the integrin complex and reverses the inhibitory effect of JMP. These findings suggest a new mechanism through which N-cadherin and β1-integrins are coordinately regulated: loss of an effector from the cytoplasmic domain of N-cadherin and gain of that effector by the β1-integrin complex.

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

“…Like integrins, cadherins now seem to broadly engage many signaling systems, including the RhoA pathway described here, as well as the previously reported Rac, Erk, PKC, and Akt pathways (Lewis et al, 1994;Carmeliet et al, 1999;Pece and Gutkind, 2000). Thus, although numerous examples of cross talk in cadherin and integrin signaling have been suggested in the literature (Zhu and Watt, 1996;Arregui et al, 2000), our findings here indicate that cadherin-integrin cross talk largely depends on the ability of cadherins to profoundly affect cell mechanics. In sum, the interplay of mechanical and biochemical signals that orchestrate the dynamic physical linkages between cell-cell adhesion, cell-ECM adhesion, and cell mechanics demonstrated here constitute early hints of the mechanisms by which cells can coordinate mechanically during the complex process of morphogenesis.…”

Identification of an Invasive, N-Cadherin-Expressing Epithelial Cell Type in Endometriosis Using a New Cell Culture Model

“…This treatment also results in release of the nonreceptor tyrosine kinase Fer from cadherin and its accumulation in the integrin complex, suggesting cross-talk between these two receptor complexes. 80 In addition to the endometriotic cell lines, we also found N-cadherin-positive cells expressing cytokeratin in endometriotic lesions. These cells can be found in the majority, but not all, of the biopsies investigated so far, possibly reflecting differences in the type or developmental stage of individual biopsies.…”

Turn‐off, drop‐out: Functional state switching of cadherins

“…The juxtamembrane cadherin sequence to which p120 ctn binds is within a region required for cis clustering (Yap et al, 1998) and is adjacent to a sequence that has the potential to directly dimerize (Arregui et al, 2000;see Fig. 2).…”

“…␤-catenin and PTP1B binding domains on N-cadherin and conservation of the PTP1B site. The core ␤-catenin binding sequence defined by deletions (Kaplan et al, 2001 andSimcha et al 2001) and that defined by peptide competition (Arregui et al, 2000) are compared in Figure 2. In this figure we use the region defined by the peptide competitor.…”