MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer.

Abstract	Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor beta (TGFbeta)-mediated increases in cell invasion are dependent upon activation of the serine/threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGFbeta treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wild-type MAPKAPK2 and HSP27 both increased TGFbeta-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGFbeta-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGFbeta-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGFbeta-mediated increases in MMP-2 and cell invasion in human prostate cancer.
Authors	L Xu, S Chen, R C Bergan
Journal	Oncogene (Oncogene) Vol. 25 Issue 21 Pg. 2987-98 (May 18 2006) ISSN: 0950-9232 [Print] England
PMID	16407830 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References	HSP27 Heat-Shock Proteins HSPB1 protein, human Heat-Shock Proteins Imidazoles Intracellular Signaling Peptides and Proteins Molecular Chaperones Neoplasm Proteins Pyridines RNA, Small Interfering Recombinant Fusion Proteins Transforming Growth Factor beta Protein Kinases MAP-kinase-activated kinase 2 Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Matrix Metalloproteinase 2 SB 203580
Topics	Adenocarcinoma (enzymology, pathology) Cell Line, Tumor (drug effects, enzymology) Enzyme Activation (drug effects) HSP27 Heat-Shock Proteins Heat-Shock Proteins (physiology) Humans Imidazoles (pharmacology) Intracellular Signaling Peptides and Proteins Male Matrix Metalloproteinase 2 (metabolism) Molecular Chaperones Neoplasm Invasiveness Neoplasm Proteins (physiology) Prostatic Neoplasms (enzymology, pathology) Protein Kinases (genetics, physiology) Protein Serine-Threonine Kinases Pyridines (pharmacology) RNA Interference RNA, Small Interfering (pharmacology) Recombinant Fusion Proteins (physiology) Signal Transduction (drug effects) Transfection Transforming Growth Factor beta (physiology) p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)

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