Thrombin Up-regulates Cathepsin D which Enhances Angiogenesis, Growth, and Metastasis

Hu, Liang; Roth, Jennifer; Brooks, Peter C.; Luty, Joanna; Karpatkin, Simon

doi:10.1158/0008-5472.can-07-6276

Cited by 101 publications

(74 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concentrated samples were measured for the protein concentration by BCA protein assay reagents (Bio-Rad). Gelatin zymography was used to assess MMP9 activity (25). Briefly, 20 g of protein from each sample was mixed with SDS sample buffer in the absence of reducing reagents, which were separated on 10% SDS-polyacrylamide gels containing 0.1% gelatin.…”

Section: Methodsmentioning

confidence: 99%

“…5, A and B, show that a 24-h incubation of p38␥-expressed IEC-6 cells with both inhibitors significantly reduces the MMP9 activity and almost completely abolishes p38␥-induced invasion. SB-3CT (41) and ilomastat (25) were previously shown to decrease the MMP9 activity, which was speculated to occur via a positive feedback regulation that links MMP9 activity to its transcription (41). Although these compounds may affect additional targets, a coupling of decreased MMP9 activity with reduced invasion by both inhibitors strongly suggests a role of MMP9 in p38␥ invasive activity.…”

Section: P38␥ Controls Endogenous C-jun and Mmp9 Expression In Human mentioning

confidence: 99%

See 1 more Smart Citation

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

Mitogen-activated protein kinases (MAPKs) regulate gene expression through transcription factors. However, the precise mechanisms in this critical signal event are largely unknown. Here, we show that the transcription factor c-Jun is activated by p38␥ MAPK, and the activated c-Jun then recruits p38␥ as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion. This signaling event was initiated by hyperexpressed p38␥ that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38␥ interacting with c-Jun. p38␥ requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38␥ are required for the trans-activation of MMP9. The active p38␥/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38␥ and MMP9 expression in the primary tissues. These results reveal a new paradigm in which a MAPK acts both as an activator and a cofactor of a transcription factor to regulate gene expression leading to an invasive response. MAPKs3 (including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38s) are critical signaling cascades that convert upstream signals into biological responses such as cell proliferation, invasion, and transformation (1). MAPKs are believed to do so by phosphorylating and activating a group of transcription factors, which through binding regulatory DNA elements lead to altered gene transcription. c-Jun is a major component of the AP-1 transcription factor downstream of MAPKs, whereas AP-1 is composed of homodimers of the Jun family or its heterodimers with another transcription factor such as c-Fos to bind the consensus DNA elements TGAg/cTCA (2). c-Jun is activated by JNK through phosphorylation at Ser-63, Ser-73, Thr-91, and Thr-93, and by ERK and p38 via increased gene expression. Activated c-Jun/ AP-1 leads to a cell type-specific biological response through integrated gene expression (1). However, the exact mechanism by which c-Jun converts a MAPK activity into a target gene expression remains mostly unknown.p38 MAPKs consist of four family members (␣, ␤, ␥, and ␦) in which p38␣ is ubiquitously present, whereas p38␥ is highly expressed in certain cancers (3). In addition to well established regulatory effects in cytokine signaling and stress response, substantial evidence suggests that the p38␣ pathway functions as a tumor suppressor (4 -8). p38␥, on the other hand, is a 43-kDa protein with an unique C-terminal motif, KETXL, that can dock with the PDZ (PSD-95/Dlg/ZO-1 homology) domain of other proteins (9, 10). In contrast to p38␣, our recent studies showed that p38␥ is induced by Ras and required for Ras transformation and invasion (11, 12), indicating its oncogenic activity. The underlying mechanisms for p38␥ involvement in Ras tumorigenesis, however, have not been established. In this report, we show that p38␥ acts both as an activator and a cofactor for c-Jun in trans-activating MMP9, a critical matrix metalloprote...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: P38␥ Controls Endogenous C-jun and Mmp9 Expression In Human mentioning

confidence: 99%

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

show abstract

“…Candidate proteins were again selected based on a former gene expression study showing divergent transcript levels in monocyte subsets for MMP-25 (MT6-MMP) and TIMP-1. 11 Furthermore, the tumor promoter and matrix-degrading protease cathepsin D (CTSD) was investigated, as it has previously been reported to be induced upon monocyte maturation, 19,20 and MMP-14 (MT1-MMP) was included, since it has been specifically connected to monocyte trans-endothelial migration. 21 None of the analyzed proteases showed a preferential expression in intermediate monocytes of CRC patients prior to treatment (Fig.…”

Section: Neoadjuvant Therapy Triggers a Significant Increase In Intermentioning

confidence: 99%

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

et al. 2016

View full text Add to dashboard Cite

“…We checked these results by investigating the effect of recombinant proteolytically inactive D231N pro-cath-D on the production of endogenous LRP1b-CTF in HMF .1(-) plasmids using Lipofectamine (Gibco-BRL, Life Technologies SAS, Villebon sur Yvette, France). pcDNA3.1(-)cath-D expression plasmid encoding human pre-pro-cath-D has previously been described (Vignon et al, 1986;Glondu et al, 2001Glondu et al, , 2002Berchem et al, 2002;Laurent-Matha et al, 2005;Hu et al, 2008). fibroblasts ( Figure 3C, panel a).…”

Section: Ectopic Cath-d and Pro-cath-d Inhibit Lrp1 Rip In Cos Cells mentioning

confidence: 99%

“…Inhibition of cath-D expression in breast cancer cells decreases tumor growth and metastasis Ohri et al, 2007;Vashishta et al, 2007). Human secreted pro-cath-D stimulates breast cancer cell proliferation (Vignon et al, 1986;Fusek and Vetvicka, 1994;Vetvicka et al, 1994;Ohri et al, 2008), fibroblast outgrowth (Laurent-Matha et al, 2005) and angiogenesis (Hu et al, 2008). We have shown that a mutated catalytically inactive version of cath-D (D231N) is still mitogenic for tumor cells and fibroblasts (Glondu et al, 2001;Berchem et al, 2002;Laurent-Matha et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

View full text Add to dashboard Cite

The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1b-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231N cath-D, and pro-D231N cath-D all significantly inhibited LRP1 RIP by preventing LRP1b-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

show abstract

Thrombin Up-regulates Cathepsin D which Enhances Angiogenesis, Growth, and Metastasis

Cited by 101 publications

References 49 publications

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

Contact Info

Product

Resources

About