The hallmark of the menstrual cycle is extensive steroid-dependent tissue turnover. Estrogen mediates endometrial cell growth and structural remodeling, whereas progeserone suppresses estrogen-dependent proliferation and promotes cellular differentiation. In nonfertile cycles, tissue degradation and menstruation occur as a consequence of steroidal deprivation as the ovarian corpus luteum fails. Stromalepithelial interactions are recognized as a necesary component in mediating steroid-induced endometrial turnover. Specific mRNAs for metalloproteinases of the stromelysin family are expressed during endometrial growth and menstrual breakdown but are absent in the progestin-dominated secretory phase. This expression pattern suggss involvement of stromelysins in remodeling the extracellular matrix of the endometrium during tissue growth and breakdown and implicates progesteronE in the suppression of these enzymes. We examined the regulation of endometrial stromelysins in explant cultures and found no acute effect ofestradiol on their expression, whereas progesterone was a potent inhibitor of stromelysin expression. Progesterone also suppressed stromelysin expression in cultures ofisolated stromal cells, but epithelial cells were progesterone insensitive. Coculture ofrecombined stromal and epithelial cells restored steroidal suppression of the epithelial-specific metalloproteinase. Our data confirm that progesterone inhibits endometrial stromelysins and further demonstrate the necessity for a stromalderived factor(s) as a mediator of steroid suppression of an epithelial metalloproteinase.The human endometrium undergoes extensive estradiolinduced growth and remodeling during the proliferative phase of the menstrual cycle, followed by secretory maturation in response to postovulatory progesterone (1). This rapid and extensive degree of steroid-mediated tissue development, which rivals that of many neoplasias, appears to be a necessary component of providing an environment suitable for sustaining hemochorial placentation (2). In the absence of implantation and the continued progestational environment of pregnancy, the superficial functionalis region of the endometrium undergoes degradation and is expelled with menstrual blood flow. Several laboratories have recently described the expression of matrix metalloproteinases (MMPs) in the normal, cycling human endometrium (3-6). These enzymes degrade many components of the extracellular matrix, including proteoglycans, glycoproteins, and basement membrane collagens (7). Our studies (5, 6) identified a cell type-specific expression pattern of mRNAs coding for members of the stromelysin family only during the proliferative and premenstrual/menstrual stage of the cycle; none of the enzymes were identified during the progesterone-dominated secretory menstrual interval. This pattern of expression suggests an active role for stromelysins during growth-associated structural remodeling as well as during the extensive tissue breakdown associated with menstruation.MMPs of the st...

2؉increases trigger FA disassembly. An unexpectedly rapid flux of FAK between cytosolic and FA compartments was revealed by fluorescence recovery after photobleaching studies. In the hierarchical organization of FA-associated proteins, FAK appears as an early component in FA formation (14). The integrin/adhesion-dependent increase in FAK Tyr 397 autophosphorylation relies on intermolecular FAK transphosphorylation (15) mediated by the formation of integrin clusters. The central role of FAK in the formation of a functional FA is also emphasized by its scaffolding function, allowing direct interaction and translocation of signaling proteins such as Src, growth factor receptor binding protein-2, paxillin, phospholipase C-␥, phosphatidylinositol 3-kinase, and p130cas (16) toward FAs. Furthermore, FAK interacts with FA structural proteins, including integrins, talin, ␣-actinin and tensin, and via paxillin with both vinculin and F-actin (17). In FAK-deficient cells, reduced motility is accompanied by an increased number of FAs (18), suggesting that FAK tyrosine kinase activity is involved in the regulation of FA turnover (19).

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Integrin-associated intracellular Ca2؉ oscillations modulate cell migration, probably by controlling integrin-mediated release of the cell rear during migration. Focal adhesion kinase (FAK), via its tyrosine phosphorylation activity, plays a key role in integrin signaling. Cell migration is a cyclic process involving initial protrusion of the leading edge, formation of adhesive sites, contraction of the cell body, and release of adhesive sites at the cell rear (1). Adhesive sites are dynamic membrane structures that vary in size and composition during migration. Integrins, actin stress fibers (SFs) 1 and other structural proteins, and regulatory signaling molecules cluster at focal adhesions (2). Focal adhesions (FAs) serve as points of traction for contractile forces underlying forward cell movement and their dynamics are finely regulated. For example, FAs are highly motile in stationary fibroblasts but are largely stationary in migrating fibroblasts, thereby transducing contractile forces into movement (3). This suggests the existence of a molecular clutch that couples cytoskeleton-mediated traction and cell contraction. In human U87 astrocytoma cells, expression of the dominant negative FAK-related non-kinase domain (FRNKFocal adhesion kinase (FAK) is activated and localized at FAs upon cell adhesion to the extracellular matrix (ECM; Refs. 4 and 5). Given the abundance of FAs and the reduced migration of fibroblasts from FAK null mice (6), FAK is likely involved in FA remodeling during migration. FAK-related nonKinase (FRNK), the non-catalytic C-terminal portion of FAK containing the FA targeting sequence, is also expressed as a separate dominant negative protein (7). The differential expression of FAK and FRNK is transcriptionally regulated, each of these proteins having distinct promoters within the FAK gene (8). Although the function of endogenous FRNK is not clear, FRNK has been used to alter signaling via endogenous FAK. When overexpressed in cells, FRNK acts as a negative regulator of FAK activity, inhibiting phosphorylation of FAK and different FAK-related processes, including cell cycle progression (9, 10), cell spreading on fibronectin (7, 11), and migration (12, 13). This suggests that the inhibitory effects of FRNK in migration might arise from altered FAK localization and phosphorylation.We and others reported that migration is dependent on Ca 2ϩ signaling in astrocytoma (14)