Evidence for an extra-cellular function for protein kinase A

Shaltiel, Shmuel; Schvartz, Iris; Korc‐Grodzicki, Beatriz; Kreizman, Tamar

doi:10.1007/978-1-4615-2600-1_26

Cited by 8 publications

(13 citation statements)

References 56 publications

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“…Our earlier studies have indicated that binding of soluble vitronectin to adherent cells is sensitive to chlorate and heparitinase treatment (88), consistent with heparan sulfate proteoglycans serving as receptors for soluble vitronectin. Studies from our lab, as well as others have suggested that binding of vitronectin to sulfated proteoglycans is important in modulating phenomena such as changes in vitronectin conformation and biological activity (8,70,73,74), extracellular half-life (23,58,60,61,88) and vitronectin-dependent clearance of thrombin-antithrombin complexes (14,15,85). Treatment of dermal fibroblasts (87,88) and HT-1080 fibrosarcoma cells (Figure 3) with chlorate to block proteoglycan sulfation results in a significant reduction in the ability of cells to bind soluble vitronectin.…”

Section: Discussionmentioning

confidence: 88%

Vitronectin's Basic Domain is a Syndecan Ligand which Functionsin transto Regulate Vitronectin Turnover

Wilkins-Port

Sanderson²,

Tominna-Sebald³

et al. 2003

Cell Communication & Adhesion

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During the process of tissue remodeling, vitronectin (Vn) is deposited in the extracellular matrix where it plays a key role in the regulation of pericellular proteolysis and cell motility. In previous studies we have shown that extracellular levels of vitronectin are controlled by receptormediated endocytosis and that this process is dependent upon vitronectin binding to sulfated proteoglycans. We have now identified vitronectin's 12 amino acid "basic domain" which is contained within the larger 40 amino acid heparin binding domain, as a syndecan binding site. Recombinant vitronectins representing wild type vitronectin (rVn) and vitronectin with the basic domain deleted (rVn 347-358) were prepared in a baculoviral expression system. The rVn as well as a glutathione S-transferase (GST) fusion protein, consisting of vitronectin's 40 amino acid heparin binding domain (GST-VnHBD), exhibited dose dependent binding to HT-1080 cell surfaces, which was attenuated following deletion of the basic domain. In addition, GST-VnHBD supported both HT-1080 and dermal fibroblast cell adhesion, which was also dependent upon the basic domain. Similarly, ARH-77 cells transfected with syndecans -1, -2, or -4, but not Glypican-1, adhered to GST-VnHBD coated wells, while adhesion of these same cells was lost following deletion of the basic domain. HT-1080 cells were unable to degrade rVn 347-358. Degradation of rVn 347-358 was completely recovered in the presence of GST-VnHBD but not in the presence of GST-VnHBD 347-358. These results indicate that turnover of soluble vitronectin requires ligation of vitronectin's basic domain and that this binding event can work in trans to regulate vitronectin degradation.

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Section: Discussionmentioning

confidence: 88%

Vitronectin's Basic Domain is a Syndecan Ligand which Functionsin transto Regulate Vitronectin Turnover

Wilkins-Port

Sanderson²,

Tominna-Sebald³

et al. 2003

Cell Communication & Adhesion

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“…1 I (g) in a rabbit given ureatreated affinity for heparin, so influencing its distribution and fractional catabolism. In vitro, phosphorylated vitronectin shows reduced affinity for PAI-1 [17]. The heparin-binding domain where phosphorylation of vitronectin by protein kinase A occurs is necessary for multimer formation and might stabilize the tertiary structure of the native form [25].…”

Section: Discussionmentioning

confidence: 99%

“…Insertion of a phosphate into this highly basic region of the molecule could influence its conformation, self-association and interaction with other molecules; it has been shown, for example, to decrease the affinity of vitronectin for PAI-1 [17].…”

Section: Introductionmentioning

confidence: 99%

The behaviour of human vitronectin in vivo: effects of complement activation, conformation and phosphorylation

Peake

Greenstein

Pussell

et al. 1996

Clinical and Experimental Immunology

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SUMMARYWe examined the behaviour in vivo of native, specifically phosphorylated, and multimeric vitronectin to determine the effects of these modifications on its turnover, distribution and molecular behaviour. In normal rabbits, the plasma half-life (T 1/2 ) of antigenically detected vitronectin was 8 . 00 . In vitro, phosphorylation had no effect on the affinity of vitronectin for heparin-Sepharose, while complement activation with cobra venom factor (CVF) led to a two-fold enrichment of 32 P-vitronectin within the SC5b-9 complex. In vivo CVF caused a rapid decrease in the circulating levels of 32 P-vitronectin and was accompanied by the prompt appearance of a high mol. wt species consistent with SC5b-9. Despite specific incorporation of 32 P-vitronectin into SC5b-9, both forms of the molecule had similar inhibitory effects on C9-mediated haemolysis of EAC1-7 cells. Urea-activated vitronectin was rapidly cleared from circulation with less than 15% remaining after 1 h while protein-bound label accumulated in the spleen, lung and liver. These results demonstrate that vitronectin is a rapidly metabolized protein whose in vivo behaviour is markedly altered when phosphorylated or activated to form multimers and SC5b-9.

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“…It may have a possible role in malignancy, as it is expressed at high levels in tumors [168]. Previous work showed that PKA can phosphorylate vitronectin at serine 378, herewith affecting its conformation [169,170]. By this phosphorylation, vitronectin was converted from an antifibrinolytic agent that prevents the occurrence of undesired fibrinolysis into a profibrinolytic form that initiates the solubilisation of blood clots [160].…”

Section: Phosphorylation Of Fibrinogen Vitronectin and The Impactmentioning

confidence: 99%

Prostasome Involvement in the Development and Growth of Prostate Cancer~!2009-07-10~!2009-12-09~!2010-02-11~!

Babiker¹,

Ronquist²,

Nilsson³

et al. 2010

TOPCANJ

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Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.Keywords: ATPase, CD59, CK, complement, DU145, Extracellular phosphorylation, LNCaP, PC-3, PKA, PKC, prostasomes, prostate cancer, protein kinases, tissue factor. I. GENERAL BACKGROUND A. Prostate CancerProstate cancer is the most prevalent noncutaneous cancer in many of the Western countries and is the second leading cause of cancer death in men in USA [1]. The introduction of prostate specific antigen (PSA) in the latter half of 1980s as a biochemical marker of prostate cancer in serum signified a radical change of the pattern of prostate cancer diagnosis. It meant that more cases were detected at an early stage and substantially fewer at advanced stages [2] [3]. There are also studies showing that increasing incidence of prostate can...

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Evidence for an extra-cellular function for protein kinase A

Cited by 8 publications

References 56 publications

Vitronectin's Basic Domain is a Syndecan Ligand which Functionsin transto Regulate Vitronectin Turnover

Vitronectin's Basic Domain is a Syndecan Ligand which Functionsin transto Regulate Vitronectin Turnover

The behaviour of human vitronectin in vivo: effects of complement activation, conformation and phosphorylation

Prostasome Involvement in the Development and Growth of Prostate Cancer~!2009-07-10~!2009-12-09~!2010-02-11~!

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