SUMMARY Deregulation of SHP2 is associated with malignant diseases as well as developmental disorders. Although SHP2 is required for full activation of RAS signaling, other potential roles in cell physiology have not been elucidated. Here we show that SHP2 dephosphorylates parafibromin/Cdc73, a core component of the RNA polymerase II-associated factor (PAF) complex. Parafibromin is known to act as a tumor suppressor that inhibits cyclin D1 and c-myc by recruiting SUV39H1 histone methyltransferase. However, parafibromin can also act in the opposing direction by binding β-catenin, thereby activating pro-mitogenic/oncogenic Wnt signaling. We found that, upon tyrosine dephosphorylation by SHP2, parafibromin acquires the ability to stably bind β-catenin. The parafibromin/β-catenin interaction overrides parafibromin/SUV39H1-mediated transrepression and induces expression of Wnt target genes, including cyclin D1 and c-myc. Hence, SHP2 governs the opposing functions of parafibromin, deregulation of which may cause the development of tumors or developmental malformations.

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a risk factor for a variety of atherosclerotic disorders including coronary heart disease. In the current study, we report that incubation of cultured human umbilical vein or coronary artery endothelial cells with Lp(a) elicits a dramatic rearrangement of the actin cytoskeleton characterized by increased central stress fiber formation and redistribution of focal adhesions. These effects are mediated by the apolipoprotein(a) (apo(a)) component of Lp(a) since incubation of apo(a) with the cells evoked similar cytoskeletal rearrangements, while incubation with low density lipoprotein had no effect. Apo(a) also produced a time-dependent increase in transendothelial permeability. The cytoskeletal rearrangements evoked by apo(a) were abolished by C3 transferase, which inhibits Rho, and by Y-27632, an inhibitor of Rho kinase. In addition to actin cytoskeleton remodeling, apo(a) was found to cause VE-cadherin disruption and focal adhesion molecule reorganization in a Rho-and Rho kinase-dependent manner. Cell-cell contacts were found to be regulated by Rho and Rac but not Cdc42. Apo(a) caused a transient increase in the extent of myosin light chain phosphorylation. Finally apo(a) did not evoke increases in intracellular calcium levels, although the effects of apo(a) on the cytoskeleton were found to be calcium-dependent. We conclude that the apo(a) component of Lp(a) activates a Rho/Rho kinasedependent intracellular signaling cascade that results in increased myosin light chain phosphorylation with attendant rearrangements of the actin cytoskeleton. We propose that the resultant increase in endothelial permeability caused by Lp(a) may help explain the atherosclerotic risk posed by elevated concentrations of this lipoprotein.The vascular endothelium acts as a pivotal regulator in vessel wall homeostasis by forming a selective barrier between components of the blood and extravascular tissues. Increasing evidence suggests that atypical endothelial function is a key event in the initial stages of atherosclerosis development. More specifically, enhanced endothelial cell permeability and the expression of a procoagulant, antifibrinolytic, and proinflammatory phenotype by the endothelium is thought to be a crucial event in the onset of this disease (1). Various physiological agents have been identified that elicit some manifestations of endothelial dysfunction. These include growth factors, inflammatory cytokines such as tumor necrosis factor-␣ (2), vasoactive substances such as thrombin (3), and mildly oxidized, but not native, low density lipoprotein (LDL) 1 (4). Many of these agents alter the permeability of the endothelium by stimulating cell contraction, thereby increasing the size of intercellular gaps and facilitating entry of inflammatory cells and atherogenic lipoproteins. The mechanism by which these agents are able to alter properties of the endothelium has received much attention. Endothelial cell contraction is mediated by interactions between actin filam...