Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27(kip1) affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27(kip1) activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27(kip1) or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27(kip1) expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27(kip1) in different subcellular compartments.

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The α4/α9 integrins directly engage the ECM glycoprotein EMILIN1 to inhibit skin cell proliferation upstream of TGF-β signaling.

Lymphatic-vasculature function critically depends on extracellular matrix (ECM) and on its connections with lymphatic endothelial cells (LECs). However, the composition and the architecture of ECM have not been fully taken into consideration in studying the biology and the pathology of the lymphatic system. EMILIN1, an elastic microfibril-associated protein, is highly expressed by LECs in vitro and colocalizes with lymphatic vessels in several mouse tissues. A comparative study between WT and Emilin1 ؊/؊ mice highlighted the fact that Emilin1 deficiency in both CD1 and C57BL/6 backgrounds results in hyperplasia, enlargement, and frequently an irregular pattern of superficial and visceral lymphatic vessels and in a significant reduction of anchoring filaments. Emilin1-deficient mice also develop larger lymphangiomas than WT mice. Lymphatic vascular morphological alterations are accompanied by functional defects, such as mild lymphedema, a highly significant drop in lymph drainage, and enhanced lymph leakage. Our findings demonstrate that EMILIN1 is involved in the regulation of the growth and in the maintenance of the integrity of lymphatic vessels, a fundamental requirement for efficient function. The phenotype displayed by Emilin1 ؊/؊ mice is the first abnormal lymphatic phenotype associated with the deficiency of an ECM protein and identifies EMILIN1 as a novel local regulator of lymphangiogenesis.Lymphatic and blood vascular systems have distinct structural characteristics that reflect their specific and complementary functions. The lymphatic vasculature represents a second circulatory system and maintains tissue fluid homeostasis; it plays a major role in the absorption of dietary fat and in immune response, transporting lymphocytes and antigen-presenting cells to regional lymph nodes; finally, it provides routes for tumor metastasis (8). The lymphatic system consists of a complex network of lymphatic capillaries, which are uniquely adapted for the uptake of protein-rich lymph from tissue interstitium, and collecting lymphatic vessels that transport lymph back to the blood vascular system. The latter are surrounded by a basement membrane and smooth muscle cells, which are less organized than in blood vessels and, in addition, have intraluminal valves, which prevent lymph backflow (26). By contrast, lymphatic capillaries are blind-end vessels, lined by a single thin layer of overlapping lymphatic endothelial cells (LECs) directly connected to the surrounding extracellular matrix (ECM) by means of anchoring elastic filaments (18). These structures play a fundamental role in lymphatic-vessel function and represent one of the main distinguishing features between lymphatic and blood capillaries. When interstitial fluid pressure increases, anchoring filaments exert tension on LECs, thereby widening the capillary lumen and opening the overlapping cell junctions, which enable fluid and macromolecule uptake and cell entry. It is thought that abnormalities of anchoring filaments may reduce adsorption from the intersti...