Plasminogen binding and cancer promises and pitfalls

Ranson, Marie; Andronicos, Nicholas M.

doi:10.2741/1044

Cited by 57 publications

(92 citation statements)

References 122 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The lack of either plasminogen acquisition or activation in human serum by NS88.2prp suggests that for GAS expressing plasminogen binding M proteins (PAMpositive GAS), α-enolase and GAPDH which likely interact with kringle domains 4 and 5 of plasminogen (11,39), do not significantly contribute to plasminogen binding and activation. Plasminogen binding M proteins interact with kringle domain 2 of plasminogen and are specifically co-inherited with the sub-cluster 2b allele of streptokinase (8).…”

Section: Discussionmentioning

confidence: 99%

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

Sanderson-Smith¹,

Dinkla²,

Cole³

et al. 2008

FASEB j.

View full text Add to dashboard Cite

MJ, M protein mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate, The FASEB Journal, 22(8), 2008, 2715-2722 M protein mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate AbstractThe human protease plasmin plays a crucial role in the capacity of the group A streptococcus (Streptococus pyogenes; GAS) to initiate invasive disease. The GAS strain NS88.2 was isolated from a case of bacteremia from the Northern Territory of Australia, a region with high rates of GAS invasive disease. Mutagenesis of the NS88.2 plasminogen binding M protein Prp was undertaken to examine the contribution of plasminogen binding and cell surface plasmin acquisition to virulence. The isogenic mutant NS88.2prp was engineered whereby four amino acid residues critical for plasminogen binding were converted to alanine codons in the GAS genome sequence. The mutated residues were reverse complemented to the wildtype sequence to construct GAS strain NS88.2prpRC. In comparison to NS88.2 and NS88.2prpRC, the NS88.2prp mutant exhibited significantly reduced ability to bind human plasminogen and accumulate cell surface plasmin activity during growth in human plasma. Utilising a humanised plasminogen mouse model of invasive infection, we demonstrate that the capacity to bind plasminogen and accumulate surface plasmin activity plays an essential role in GAS virulence. ABSTRACTThe human protease plasmin plays a crucial role in the capacity of the group A streptococcus (Streptococus pyogenes; GAS) to initiate invasive disease. The GAS strain NS88.2 was isolated from a case of bacteremia from the Northern Territory of Australia, a region with high rates of GAS invasive disease. Mutagenesis of the NS88.2 plasminogen binding M protein Prp was undertaken to examine the contribution of plasminogen binding and cell surface plasmin acquisition to virulence.The isogenic mutant NS88.2prp was engineered whereby four amino acid residues critical for plasminogen binding were converted to alanine codons in the GAS genome sequence. The mutated residues were reverse complemented to the wildtype sequence to construct GAS strain NS88.2prpRC. In comparison to NS88.2 and NS88.2prpRC, the NS88.2prp mutant exhibited significantly reduced ability to bind human plasminogen and accumulate cell surface plasmin activity during growth in human plasma. Utilising a humanised plasminogen mouse model of invasive infection, we demonstrate that the capacity to bind plasminogen and accumulate surface plasmin activity plays an essential role in GAS virulence.

show abstract

Section: Discussionmentioning

confidence: 99%

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

Sanderson-Smith¹,

Dinkla²,

Cole³

et al. 2008

FASEB j.

View full text Add to dashboard Cite

show abstract

“…uPA is a potent marker of metastatic capacity in multiple human tumors and makes an attractive therapeutic target (11)(12)(13). Recent work has shown that cytotoxins attached to the PAI-2 molecule can be specifically delivered to malignant xenografts by targeting cell surface uPA (14 -17), despite the apparent high levels of endogenous PAI-1 associated with malignant carcinoma (summarized in Ref.…”

mentioning

confidence: 99%

The Urokinase/PAI-2 Complex

Croucher

Saunders

Ranson

2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The efficient inactivation of urokinase plasminogen activator (uPA) by plasminogen activator inhibitor type 2 (PAI-2) at the surface of carcinoma cells is followed by rapid endocytosis of the uPA-PAI-2 complex. We now show that one pathway of this receptormediated endocytosis is mediated via the low density lipoprotein receptor-related protein (LRP) in prostate cancer cells. Detailed biochemical analyses using ligand binding assays and surface plasmon resonance revealed a novel and distinct interaction mechanism between native, human LRP and uPA-PAI-2. As reported previously for PAI-1, inhibition of uPA by PAI-2 significantly increased the affinity of the complex for LRP (K D of 36 nM for uPA-PAI-2 versus 200 nM for uPA). This interaction was maintained in the presence of uPAR, confirming the validity of this interaction at the cell surface. However, unlike PAI-1, no interaction was observed between LRP and PAI-2 in either the stressed or the relaxed conformation. This suggests that the uPA-PAI-2-LRP interaction is mediated by site(s) within the uPA molecule alone. Thus, as inhibition of uPA by PAI-2 resulted in accelerated clearance of uPA from the cell surface possibly via its increased affinity for LRP, this represents a mechanism through which PAI-2 can clear proteolytic activity from the cell surface. Furthermore, lack of a direct interaction between PAI-2 and LRP implies that downstream signaling events initiated by PAI-1 may not be activated by PAI-2.Inhibition of urokinase plasminogen activator (uPA) 4 proteolytic activity at the cell surface is an important step in the regulation of pericellular plasminogen activation (1-4). This process is facilitated by members of the serpin (serine protease inhibitor) superfamily, most notably by plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2) (SerpinE1 and SerpinB2, respectively) (5-7). Although both are efficient uPA inhibitors, PAI-1 and PAI-2 are structurally and functionally quite distinct serpins, as recognized by their grouping into different serpin subfamily groups (6). For example, PAI-1 also has alternative non-uPA inhibitory activities that affect cell adhesion, intracellular signaling, and cell migration (8) that have not been demonstrated for PAI-2.In their classical inhibitory role, serpins interact with their target protease through an exposed peptide loop, the reactive center loop (6, 9). This acts as bait for the active site of the protease, leading to formation of an equimolar covalent complex. The formation of this complex results in extensive deformation of both the protease and the serpin (9), resulting in the conversion of the serpin from a "stressed" to a "relaxed" form. The relaxed conformation of PAI-2 and other serpins can also be induced by the insertion of a peptide that mimics the reactive center loop (10).uPA is a potent marker of metastatic capacity in multiple human tumors and makes an attractive therapeutic target (11-13). Recent work has shown that cytotoxins attached to the PAI-2 molecule can be specifically delivered to ...

show abstract

“…There is extensive experimental, preclinical, and clinical data that supports the role of the uPA system as a marker of malignancy (2,3,13). We have previously shown the potential of a-PAI-2 as an efficacious anti-uPA -targeted therapy against metastatic breast carcinoma models (16 -18).…”

Section: Discussionmentioning

confidence: 99%

“…These data are strongest for breast cancer but there is good evidence for prognostic significance in multiple tumor types (3). Furthermore, localization studies indicate that quiescent, normal, or benign tissues do not express significant levels of uPA/ uPAR or PAI-1 compared with invasive carcinoma and metastases (2). Depending on the carcinoma type, components of the uPA system are often expressed by tumor stromal cells (4) that may be highly supportive of the tumor (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…In this system, uPA binds to its specific receptor (uPAR) and efficiently converts plasminogen into the broad-spectrum protease plasmin, which promotes cell invasion and metastasis by directly and indirectly degrading extracellular matrix (1,2). The proteolytic activity and turnover of uPA is regulated by plasminogen activator inhibitor types 1 and 2 (PAI-1 and PAI-2; SerpinE1, SerpinB2, respectively; refs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma

Stutchbury

Al-Ejeh

Stillfried

et al. 2007

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by 213 Bi-labeled plasminogen activator inhibitor type 2 (A-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of A-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human A-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg A-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/ kg/d Â 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d Â 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of A-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies.

show abstract

Plasminogen binding and cancer promises and pitfalls

Cited by 57 publications

References 122 publications

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

The Urokinase/PAI-2 Complex

Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma

Contact Info

Product

Resources

About