p120-Catenin is required for mouse vascular development.

RATIONALE: p120-catenin (p120) is an armadillo family protein that binds to the cytoplasmic domain of classical cadherins and prevents cadherin endocytosis. The role of p120 in vascular development is unknown. OBJECTIVE: The purpose of this study is to examine the role of p120 in mammalian vascular development by generating a conditionally mutant mouse lacking endothelial p120 and determining the effects of the knockout on vasculogenesis, angiogenic remodeling, and the regulation of endothelial cadherin levels. METHODS AND RESULTS: A conditional Cre/loxP gene deletion strategy was used to ablate p120 expression, using the Tie2 promoter to drive endothelial Cre recombinase expression. Mice lacking endothelial p120 died embryonically beginning at embryonic day 11.5. Major blood vessels appeared normal at embryonic day 9.5. However, both embryonic and extraembryonic vasculature of mutant animals were disorganized and displayed decreased microvascular density by embryonic day 11.5. Importantly, both vascular endothelial cadherin and N-cadherin levels were significantly reduced in vessels lacking p120. This decrease in cadherin expression was accompanied by reduced pericyte recruitment and hemorrhaging. Furthermore, p120-null cultured endothelial cells exhibited proliferation defects that could be rescued by exogenous expression of vascular endothelial cadherin. CONCLUSIONS: These findings reveal a fundamental role for p120 in regulating endothelial cadherin levels during vascular development, as well as microvascular patterning, vessel integrity, and endothelial cell proliferation. Loss of endothelial p120 results in lethality attributable to decreased microvascular density and hemorrhages.

Role of p120-catenin in cadherin trafficking.

p120-catenin (p120) has emerged over the past several years as an important regulatory component of the cadherin adhesive complex. A core function of p120 in mammalian cells is to stabilize cadherins at the cell membrane by modulating cadherin membrane trafficking and degradation. In this way, p120 levels act as a set point mechanism that tunes cell-cell adhesive interactions. The primary control point for this regulatory activity appears to be at the level of cadherin internalization from the plasma membrane, although p120 may also impact other aspects of cadherin trafficking and turnover. In the following review, the general mechanisms of cadherin trafficking are discussed, and models for how p120 may influence cadherin membrane dynamics are presented. In one model, p120 may function as a "cap" to bind the cadherin cytoplasmic tail and prevent cadherin interactions with endocytic membrane trafficking machinery. Alternatively, p120 may stabilize cell junctions or regulate membrane trafficking machinery through interactions with small GTPases such as Rho A, Rac and Cdc42. Through these mechanisms p120 exerts influence over a wide range of biological processes that are dependent upon tight regulation of cell surface cadherin levels.

p120-catenin and ß-catenin differentially regulate cadherin adhesive function.

Vascular endothelial (VE)-cadherin, the major adherens junction adhesion molecule in endothelial cells, interacts with p120-catenin and ß-catenin through its cytoplasmic tail. However, the specific functional contributions of the catenins to the establishment of strong adhesion are not fully understood. Here we use bioengineering approaches to identify the roles of cadherin-catenin interactions in promoting strong cellular adhesion and the ability of the cells to spread on an adhesive surface. Our results demonstrate that the domain of VE-cadherin that binds to ß-catenin is required for the establishment of strong steady-state adhesion strength. Surprisingly, p120 binding to the cadherin tail had no effect on the strength of adhesion when the available adhesive area was limited. Instead, the binding of VE-cadherin to p120 regulates adhesive contact area in a Rac1-dependent manner. These findings reveal that p120 and ß-catenin have distinct but complementary roles in strengthening cadherin-mediated adhesion.