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Ectokinases as novel cancer markers and drug targets in cancer therapy.

Yalak G, Vogel V - Cancer Med (2014)

Bottom Line: While small-molecule kinase inhibitors became the most prominent anticancer drugs, novel combinatorial strategies need to be developed as the fight against cancer is not yet won.Our analysis of proteomic data reveals that fibronectin is heavily phosphorylated in cancer tissues particularly within its growth factor binding sites and on domains that regulate fibrillogenesis.We are thus making the case that cancer is not only a disease of cells but also of the ECM.

View Article: PubMed Central - PubMed

Affiliation: Harvard Medical School/Harvard School of Dental Medicine, Department of Developmental Biology, Harvard University, Boston, Massachusetts, 02115; Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Switzerland.

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Experimentally verified phosphorylation sites on fibronectin. Schematic representation of plasma fibronectin with modules type I (gray), type II (turquoise), and type III (orange). (A) Locations of various bacterial and cell binding sites on the fibronectin monomer. (B) Experimentally identified phosphorylation sites by mass spectrometry techniques as retrieved from protein data banks Phosida, PhosphoSitePlus, PhosphoNet, HPRD, dbPTM, and UniProt for human Fn (P02751). (C) Locations of protein binding sites on the fibronectin monomer with a special focus on matrix metalloproteinases (MMPs).
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fig02: Experimentally verified phosphorylation sites on fibronectin. Schematic representation of plasma fibronectin with modules type I (gray), type II (turquoise), and type III (orange). (A) Locations of various bacterial and cell binding sites on the fibronectin monomer. (B) Experimentally identified phosphorylation sites by mass spectrometry techniques as retrieved from protein data banks Phosida, PhosphoSitePlus, PhosphoNet, HPRD, dbPTM, and UniProt for human Fn (P02751). (C) Locations of protein binding sites on the fibronectin monomer with a special focus on matrix metalloproteinases (MMPs).

Mentions: Postulating that massive necrosis might temporarily upregulate ectokinase activity in extracellular space, we recently mined published proteomic data and found a significant upregulation of phosphorylated residues in tissue samples from cancer patients 30. This included the phosphorylation of ECM proteins, as well as of cell surface and extracellular domains of transmembrane proteins. Screening more than 60 different extracellular proteins revealed that nearly all can occur in phosphorylated states 30. Most compelling was the finding that the integrin subunits α4 and β1, two key players in cancer progression and signaling, were found in tissue samples to be phosphorylated in their extracellular domains 30,42–44. Since fibronectin 45–47 which is a key component of the ECM is known to be highly upregulated in cancer 48–53, we further analyzed published proteomic data and found that fibronectin is indeed heavily phosphorylated in clinical cancer tissue samples (Fig.2, Table2). Heavily phosphorylated regions in fibronectin include and are associated with growth factor binding sites (FnIII4, FnIII13-14) and with domains that regulate fibronectin fibrillogenesis. This is an important finding since growth factor signaling and ECM fibrillogenesis are essential regulators in cancer malignancy and progression 22. In addition to fibronectin, elevated levels of phosphorylated fibrinogen A are found in the plasma from patients with stage III or IV ovarian cancer compared to healthy controls 54.


Ectokinases as novel cancer markers and drug targets in cancer therapy.

Yalak G, Vogel V - Cancer Med (2014)

Experimentally verified phosphorylation sites on fibronectin. Schematic representation of plasma fibronectin with modules type I (gray), type II (turquoise), and type III (orange). (A) Locations of various bacterial and cell binding sites on the fibronectin monomer. (B) Experimentally identified phosphorylation sites by mass spectrometry techniques as retrieved from protein data banks Phosida, PhosphoSitePlus, PhosphoNet, HPRD, dbPTM, and UniProt for human Fn (P02751). (C) Locations of protein binding sites on the fibronectin monomer with a special focus on matrix metalloproteinases (MMPs).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380966&req=5

fig02: Experimentally verified phosphorylation sites on fibronectin. Schematic representation of plasma fibronectin with modules type I (gray), type II (turquoise), and type III (orange). (A) Locations of various bacterial and cell binding sites on the fibronectin monomer. (B) Experimentally identified phosphorylation sites by mass spectrometry techniques as retrieved from protein data banks Phosida, PhosphoSitePlus, PhosphoNet, HPRD, dbPTM, and UniProt for human Fn (P02751). (C) Locations of protein binding sites on the fibronectin monomer with a special focus on matrix metalloproteinases (MMPs).
Mentions: Postulating that massive necrosis might temporarily upregulate ectokinase activity in extracellular space, we recently mined published proteomic data and found a significant upregulation of phosphorylated residues in tissue samples from cancer patients 30. This included the phosphorylation of ECM proteins, as well as of cell surface and extracellular domains of transmembrane proteins. Screening more than 60 different extracellular proteins revealed that nearly all can occur in phosphorylated states 30. Most compelling was the finding that the integrin subunits α4 and β1, two key players in cancer progression and signaling, were found in tissue samples to be phosphorylated in their extracellular domains 30,42–44. Since fibronectin 45–47 which is a key component of the ECM is known to be highly upregulated in cancer 48–53, we further analyzed published proteomic data and found that fibronectin is indeed heavily phosphorylated in clinical cancer tissue samples (Fig.2, Table2). Heavily phosphorylated regions in fibronectin include and are associated with growth factor binding sites (FnIII4, FnIII13-14) and with domains that regulate fibronectin fibrillogenesis. This is an important finding since growth factor signaling and ECM fibrillogenesis are essential regulators in cancer malignancy and progression 22. In addition to fibronectin, elevated levels of phosphorylated fibrinogen A are found in the plasma from patients with stage III or IV ovarian cancer compared to healthy controls 54.

Bottom Line: While small-molecule kinase inhibitors became the most prominent anticancer drugs, novel combinatorial strategies need to be developed as the fight against cancer is not yet won.Our analysis of proteomic data reveals that fibronectin is heavily phosphorylated in cancer tissues particularly within its growth factor binding sites and on domains that regulate fibrillogenesis.We are thus making the case that cancer is not only a disease of cells but also of the ECM.

View Article: PubMed Central - PubMed

Affiliation: Harvard Medical School/Harvard School of Dental Medicine, Department of Developmental Biology, Harvard University, Boston, Massachusetts, 02115; Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Switzerland.

Show MeSH
Related in: MedlinePlus