TY - JOUR
T1 - Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells
AU - Han, Qiwei
AU - Leng, Jay
AU - Bian, Dafang
AU - Mahanivong, Chitladda
AU - Carpenter, Kevin A.
AU - Pan, Zhixing K.
AU - Han, Jiahuai
AU - Huang, Shuang
PY - 2002/12/13
Y1 - 2002/12/13
N2 - We reported previously that down-regulating or functionally blocking αv integrins inhibits endogenous p38 mitogen-activated protein kinase (MAPK) activity and urokinase plasminogen activator (uPA) expression in invasive MDA-MB-231 breast cancer cells whereas engaging αv integrins with vitronectin activates p38 MAPK and up-regulates uPA expression (Chen, J., Baskerville, C., Han, Q., Pan, Z., and Huang, S. (2001) J. Biol. Chem. 276, 47901-47905). Currently, it is not clear what upstream and downstream signaling molecules of p38 MAPK mediate αv integrin-mediated uPA up-regulation. In the present study, we found that αv integrin ligation activated small GTPase Rac1 preferentially, and dominant negative Rac1 inhibited αv integrin-mediated p38 MAPK activation. Using constitutively active MAPK kinases, we found that both constitutively active MKK3 and MKK6 mutants were able to activate p38 MAPK and up-regulate uPA expression, but only dominant negative MKK3 blocked αv integrin-mediated p38 MAPK activation and uPA up-regulation. These results suggest that MKK3, rather than MKK6, mediates αv integrin-induced p38 MAPK activation. Among the potential downstream effectors of p38 MAPK, we found that only MAPK-activated protein kinase 2 affects αv integrin-mediated uPA up-regulation significantly. Finally, using β-globin reporter gene constructs containing uPA mRNA 3′-untranslated region (UTR) and adenosine/uridine-rich elements-deleted 3′-UTR, we demonstrated that p38 MAPK/MAPK-activated protein kinase 2 signaling pathway regulated uPA mRNA stability through a mechanism involving the adenosine/uridine-rich elements sequence in 3′-UTR of uPA mRNA.
AB - We reported previously that down-regulating or functionally blocking αv integrins inhibits endogenous p38 mitogen-activated protein kinase (MAPK) activity and urokinase plasminogen activator (uPA) expression in invasive MDA-MB-231 breast cancer cells whereas engaging αv integrins with vitronectin activates p38 MAPK and up-regulates uPA expression (Chen, J., Baskerville, C., Han, Q., Pan, Z., and Huang, S. (2001) J. Biol. Chem. 276, 47901-47905). Currently, it is not clear what upstream and downstream signaling molecules of p38 MAPK mediate αv integrin-mediated uPA up-regulation. In the present study, we found that αv integrin ligation activated small GTPase Rac1 preferentially, and dominant negative Rac1 inhibited αv integrin-mediated p38 MAPK activation. Using constitutively active MAPK kinases, we found that both constitutively active MKK3 and MKK6 mutants were able to activate p38 MAPK and up-regulate uPA expression, but only dominant negative MKK3 blocked αv integrin-mediated p38 MAPK activation and uPA up-regulation. These results suggest that MKK3, rather than MKK6, mediates αv integrin-induced p38 MAPK activation. Among the potential downstream effectors of p38 MAPK, we found that only MAPK-activated protein kinase 2 affects αv integrin-mediated uPA up-regulation significantly. Finally, using β-globin reporter gene constructs containing uPA mRNA 3′-untranslated region (UTR) and adenosine/uridine-rich elements-deleted 3′-UTR, we demonstrated that p38 MAPK/MAPK-activated protein kinase 2 signaling pathway regulated uPA mRNA stability through a mechanism involving the adenosine/uridine-rich elements sequence in 3′-UTR of uPA mRNA.
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U2 - 10.1074/jbc.M209542200
DO - 10.1074/jbc.M209542200
M3 - Article
C2 - 12377770
AN - SCOPUS:2242463086
SN - 0021-9258
VL - 277
SP - 48379
EP - 48385
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 50
ER -