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Regulation of plasminogen activator inhibitor‐1 secretion by urokinase and tissue plasminogen activator in rat epithelioid‐type smooth muscle cells
Author(s) -
Lau Herbert K. F.,
Ho Joanne
Publication year - 2002
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2002.03402.x
Subject(s) - mapk/erk pathway , protein kinase c , plasminogen activator , signal transduction , microbiology and biotechnology , activator (genetics) , kinase , protein kinase a , tyrosine kinase , secretion , proto oncogene tyrosine protein kinase src , proteases , mitogen activated protein kinase , biology , chemistry , receptor , biochemistry , endocrinology , enzyme
Summary. Tissue plasminogen activator (tPA) and urokinase (uPA) are targets of plasminogen activator inhibitor‐1 (PAI‐1) inhibition. We have previously shown that both proteases can also induce PAI‐1 secretion in rat smooth muscle cells (SMCs). We now report that both proteases appear to use very similar cellular mechanisms for signal transduction. They induced PAI‐1 secretion using a pathway(s) involving protein kinase C (PKC). They also activated the Raf/Mek/mitogen‐activated protein kinase (MAPK) pathway, which lies downstream of PKC activation. Activation of protein kinase A (PKA), however, lowered PAI‐1 secretion induced by uPA and tPA, as a result of an inhibition of the PKC pathway and inhibition of Raf, Mek and MAPK phosphorylations. Src and syk family non‐receptor tyrosine kinases (TK) were also involved in PAI‐1 induction. The mechanisms of interaction of these tyrosine kinases with other pathways appeared to be quite different: src appeared to act within the PKC and PKA pathways, while syk operated independently of these pathways. Furthermore, whereas src inhibition resulted in inhibition of Raf/Mek/Erk phosphorylations, syk inhibition could only inhibit Mek and Erk phosphorylations but not the phosphorylation of Raf. These multiple pathways utilized by uPA and tPA to modulate PAI‐1 secretion might be involved in determining the proteolytic or antiproteolytic potential of the SMCs under different pathophysiological conditions.