Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases.

Abstract

Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-src showed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in the src homology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.

RalA requirement for v-Src- and v-Ras-induced tumorigenicity and overproduction of urokinase-type plasminogen activator: involvement of metalloproteases

“…uPA production is upregulated in v-Src-and v-Ras-transformed NIH3T3 cells Several reports have described increases in uPA production in response to transformation by v-Src and v-Ras (Bell et al, 1993;Silberman et al, 1997). To establish whether uPA production is elevated in NIH3T3 cells in response to v-Src and v-Ras, we examined uPA expression levels in parental, and in vSrc-, and v-Ras-transformed NIH3T3 cells.…”

“…Tumor proteases like uPA and MMPs have been reported to be upregulated upon transformation by vSrc and v-Ras (Sato et al, 1993;Bell et al, 1993;Silberman et al, 1997;. Signaling pathways activated by v-Src and v-Ras (Burgering and Bos, 1995) include those involving phosphatidylinositol-3-kinase (Carpenter and Cantley, 1996), protein kinase C (Song et al, 1991), Raf-1 (Blobe et al, 1994) the extracellular regulated kinases (ERK-1 and 2) (Burgering and Bos, 1995) and phospholipase D (PLD) (Song et al, 1991).…”

Src Induces Urokinase Receptor Gene Expression and Invasion/Intravasation via Activator Protein-1/p-c-Jun in Colorectal Cancer

“…Equally important, v-src also increases the expression of urokinase, which is the ligand for the u-PAR, and this induction requires the catalytic activity of the protein tyrosine kinase and its plasma membrane localization (37). Transforming growth factor-h1 -and Smad2/3-dependent synthesis of the u-PA -specific inhibitor PAI-1 has been shown to be negatively regulated by Src (38), suggesting Src to promote proteolytic activity.…”

Progression of familial adenomatous polyposis (FAP) colonic cells after transfer of the src or polyoma middle T oncogenes: cooperation between src and HGF/Met in invasion

“…Oncogenic src was previously shown to modulate many effector systems involved in cell invasion and motility, namely cell-cell contacts, cell-matrix interactions and proteases, e.g. transin, cathepsin and urokinase plasminogen activator (Gal and Gottesman, 1986;Bell et al, 1993). For example, v-src regulates the expression of integrins and extracellular matrix components, which play a major role in Met receptor signalling and HGF bioavailability (Plantefaber and Hynes, 1989;Santos et al, 1993).…”