Phosphorylation of human plasminogen activators and plasminogen

Barlati, Sergio; Petro, Giuseppina De; Bona, Chiara; Paracini, F; Tonelli, Mariella

doi:10.1016/0014-5793(95)00312-w

Cited by 8 publications

(13 citation statements)

References 28 publications

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“…However, the pI of Pg 2ε is more acidic [24], suggesting an additional secondary modification of its structure which may be critical for its capacity to induce the expression of MMP-9. This shift in the pI of Pg 2ε may be associated with phosphorylation of the Pg molecule [63]. In this context, a shift in the pI of u-PA from 9.2 to 7.6, secondary to the phosphorylation of Tyr and Ser residues, is associated with the activation of pp60 src and of protein kinase C in metastatic tumour cells [64][65][66].…”

Section: Discussionmentioning

confidence: 99%

Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells

Gonzalez-Gronow¹,

Grenett²,

Weber³

et al. 2001

Biochem. J.

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Both plasminogen (Pg) activation and matrix metalloproteinases (MMPs) are involved in the proteolytic degradation of extracellular matrix components, a requisite event for malignant cell metastasis. The highly invasive 1-LN human prostate tumour cell line synthesizes and secretes large amounts of Pg activators and MMPs. We demonstrate here that the Pg type 2 (Pg 2) receptor in these cells is composed primarily of the membrane glycoprotein dipeptidyl peptidase IV (DPP IV). Pg 2 has six glycoforms that differ in their sialic acid content. Only the highly sialylated Pg 2γ, Pg 2δ and Pg 2ε glycoforms bind to DPP IV via their carbohydrate chains and induce a Ca# + signalling cascade ; Abbreviations used : ECM, extracellular matrix ; MMP, matrix metalloproteinase ; Pg, plasminogen ; DPP IV, dipeptidyl peptidase IV (CD26) ; u-PA, urinary-type plasminogen activator ; t-PA, tissue-type plasminogen activator ; mAb, monoclonal antibody ; FAPα, fibroblast activation protein α ; HBSS, Hanks balanced salt solution ; fura 2/AM, fura 2 acetoxymethyl ester ; 6-AHA, 6-aminohexanoic acid ; [Ca 2 + ] i , cytosolic free Ca 2 + concentration ; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. 1 To whom correspondence should be addressed (e-mail gonza002!mc.duke.edu). however, Pg 2ε alone is also able to significantly stimulate expression of MMP-9. We further demonstrate that the Pgmediated invasive activity of 1-LN cells is dependent on the availability of Pg 2ε. This is the first demonstration of a direct association between the expression of MMP-9 and the Pg activation system.

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Section: Discussionmentioning

confidence: 99%

Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells

Gonzalez-Gronow¹,

Grenett²,

Weber³

et al. 2001

Biochem. J.

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“…[40][41][42] Several studies have aimed to elucidate plasminogen structure-function relationships and interactions with other molecules, but the only PTMs described are N-and O-linked glycosylations and a phosphorylation in Ser 578. 43,44 The functional relevance of the new p-sites described here has yet to be elucidated, but they could influence plasminogen activation or plasmin enzymatic activity as it occurs with the urokinase-type plasminogen activator 45 or other enzymes involved in the coagulation cascade 46 which are regulated by phosphorylation processes. Other identified phosphoproteins related with the complement and coagulation cascades include the complement components 3 and 8, the complement factor I, the coagulation factor V, fibrinogen alpha, alpha-2 macroglobulin, kininogen, the mannan-binding lectin serine peptidase 1 and the serpins antithrombim-III, alpha-2-antiplasmin and heparin cofactor 2 ( Figure 4).…”

Section: Carrascal Et Almentioning

confidence: 98%

Characterization of the Human Plasma Phosphoproteome Using Linear Ion Trap Mass Spectrometry and Multiple Search Engines

Carrascal¹,

Ovelleiro²,

Casas³

et al. 2009

J. Proteome Res.

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Major plasma protein families play different roles in blood physiology and hemostasis and in immunodefense. Other proteins in plasma can be involved in signaling as chemical messengers or constitute biological markers of the status of distant tissues. In this respect, the plasma phosphoproteome holds potentially relevant information on the mechanisms modulating these processes through the regulation of protein activity. In this work we describe for the first time a collection of phosphopeptides identified in human plasma using immunoaffinity separation of the seven major serum protein families from other plasma proteins, SCX fractionation, and TiO(2) purification prior to LC-MS/MS analysis. One-hundred and twenty-seven phosphosites in 138 phosphopeptides mapping 70 phosphoproteins were identified with FDR < 1%. A high-confidence collection of phosphosites was obtained using a combined search with the OMSSA, SEQUEST, and Phenyx search engines.

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“…Receptor-bound urokinase is phosphorylated on tyrosine and serine residues in a human metastatic carcinomatous cell line (26). Others have shown that urokinase from human urine and from HT1080 fibrosarcoma cells contains phosphotyrosine residues, although no functional effects have been reported as yet (27,28). Recent data from this laboratory indicate that two phosphorylation sites are located within the A and B chains of pro-uPA (Ser 138/303 ) from A431 human carcinoma cells and that pro-uPA phosphorylation renders the protease unable to activate uPAR-dependent signaling in myeloid cells (29).…”

Section: /mentioning

confidence: 99%

Protein Kinase C-dependent in VivoPhosphorylation of Prourokinase Leads to the Formation of a Receptor Competitive Antagonist

Franco¹,

Massa²,

Garcı́a-Rocha³

et al. 1998

Journal of Biological Chemistry

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We recently reported that in vivo phosphorylation of urokinase-type plasminogen activator on Ser 138/303 prevents its catalytic-independent ability to promote myelomonocytic cell adherence and motility. We now show that Ca 2؉ activated, phospholipid-dependent protein kinase C from rat brain phosphorylates in vitro a peptide corresponding to prourokinase residues 133-143 (DGKKPSSPPEE) and the full-length molecule on Ser 138/ 139. The in vivo involvement of the protein kinase C isoenzyme family is supported by the finding that inhibition of kinase C activity prevents prourokinase phosphorylation on Ser 138/303 in A431 human carcinoma cells. Conversely, a short treatment of A431 cells with phorbol myristate acetate increases the extent of phosphorylated prourokinase and, concomitantly, affects its function; under these conditions, the capability of prourokinase to up-regulate U937 monocyte-like cell adherence is severely impaired, although receptor binding is unaltered. By the aid of a "phosphorylation-like" variant (Ser 138 to Glu) we show that modification of Ser 138 is sufficient to confer to prourokinase the antagonistic properties observed following in vivo stimulation of protein kinase C activity. These observations provide the first evidence that protein kinase C directs the formation of a receptor competitive antagonist by regulating the in vivo phosphorylation state of prourokinase.

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Phosphorylation of human plasminogen activators and plasminogen

Cited by 8 publications

References 28 publications

Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells

Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells

Characterization of the Human Plasma Phosphoproteome Using Linear Ion Trap Mass Spectrometry and Multiple Search Engines

Protein Kinase C-dependent in VivoPhosphorylation of Prourokinase Leads to the Formation of a Receptor Competitive Antagonist

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