Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells

Qiwei Han, Jay Leng, Dafang Bian, Chitladda Mahanivong, Kevin A. Carpenter, Zhixing K. Pan, Jiahuai Han, Shuang Huang

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)48379-48385
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number50
DOIs
StatePublished - Dec 13 2002

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Plasminogen Activators
RNA Stability
Urokinase-Type Plasminogen Activator
p38 Mitogen-Activated Protein Kinases
Integrins
Cells
Breast Neoplasms
Messenger RNA
Up-Regulation
3' Untranslated Regions
Uridine
Chemical activation
Mitogen-Activated Protein Kinases
Adenosine
Protein Kinases
Growth Substances
Vitronectin
MAP-kinase-activated kinase 2
Globins
Monomeric GTP-Binding Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. / Han, Qiwei; Leng, Jay; Bian, Dafang; Mahanivong, Chitladda; Carpenter, Kevin A.; Pan, Zhixing K.; Han, Jiahuai; Huang, Shuang.

In: Journal of Biological Chemistry, Vol. 277, No. 50, 13.12.2002, p. 48379-48385.

Research output: Contribution to journalArticle

Han, Q, Leng, J, Bian, D, Mahanivong, C, Carpenter, KA, Pan, ZK, Han, J & Huang, S 2002, 'Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells', Journal of Biological Chemistry, vol. 277, no. 50, pp. 48379-48385. https://doi.org/10.1074/jbc.M209542200
Han, Qiwei ; Leng, Jay ; Bian, Dafang ; Mahanivong, Chitladda ; Carpenter, Kevin A. ; Pan, Zhixing K. ; Han, Jiahuai ; Huang, Shuang. / Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 50. pp. 48379-48385.
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abstract = "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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AU - Leng, Jay

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AU - Mahanivong, Chitladda

AU - Carpenter, Kevin A.

AU - Pan, Zhixing K.

AU - Han, Jiahuai

AU - Huang, Shuang

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