Cell adhesion - PLAU signaling

PLAU signaling

The binding of Plasminogen activator, urokinase (PLAU (UPA)) to its glycosyl-phosphatidyl-inositol (GPI) anchored Plasminogen activator, urokinase receptor (PLAUR (UPAR) (uPAR)) mediates a variety of functions including vascular homeostasis, inflammation and tissue repair [1].

PLAU (UPA) plays a pivotal role in the regulation of cell adhesion and migration during tissue remodeling and activates intracellular signaling upon binding to certain receptors on the cell surface.

The PLAU (UPA) is an important component of the extracellular protease system because it specifically converts Plasminogen into Plasmin [2].

The tissue-type PLAU (UPA) is mainly involved in fibrinolysis, PLAU (UPA) can directly activate and be released from extracellular matrix by a number of growth factors, e.g. Hepatocyte growth factor (HGF) [3], [4]. Growth factors bind to their receptors on the cell surface and activate intracellular signaling pathways that regulate the cell behavior. HGF activates Phosphatidylinositol-3-kinase (PI3K) and V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) signaling pathways via adaptor protein GRB2-associated binding protein 1 (GAB1).

PLAUR (UPAR) is also a high-affinity receptor for the extracellular matrix protein Vitronectin. Vitronectin binds to alpha-8/beta-1 integrin and PLAUR (UPAR) to facilitate adhesion of cells. Further, binding of PLAU (UPA) to PLAUR (UPAR) strongly promotes Vitronectin binding to PLAUR (UPAR) [5]. In addition, Vitronectin binds to Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1 (PAI1) and stabilizes its inhibitory activity. PAI1 and PLAUR (UPAR) compete for binding to Vitronectin.

PLAUR (UPAR) is functionally associated with the Casein kinase 2, beta polypeptide (Casein kinase II, beta chain (Phosvitin)) that form an active complex with Casein kinase 2, alpha (Casein kinase II, alpha chains). Cell surface-located Casein kinase II can phosphorylate Vitronectin. Vitronectin is selectively phosphorylated by Casein kinase II in a PLAU (UPA)/PLAUR (UPAR)-dependent manner and phosphorylated Vitronectin is a better ligand for integrins and PLAUR (UPAR) [6]. PLAUR (UPAR) and Casein kinase II form a functional complex with the shuttle protein Nucleolin. Nucleolin is an abundant nuclear phosphoprotein that shuttles between the nucleus and cytoplasm and can translocate to the cell surface. PLAU (UPA) can induce cell proliferation through the activation of the complex that includes PLAUR (UPAR), Casein kinase II and Nucleolin [7].

PLAU (UPA) activates a number of signaling pathways that regulate cytoskeleton remodeling. On the cell surface, PLAU (UPA) binds to the high affinity receptor PLAUR (UPAR) which is located on the leading edge of the migrating cells. PLAUR (UPAR) associates on the cell surface with the integrins of the beta(2)-integrin family, and with beta(1)- and beta(3)-integrins. Binding of PLAUR (UPAR) with alpha-8/beta-1 integrin results in activation of PTK2 protein tyrosine kinase 2 (FAK1) that promotes phosphorylation of Breast cancer anti-estrogen resistance 1 (p130CAS) protein. Alpha-8/beta-1 integrin activates integrin-linked kinase (ILK), which in turn phosphorylates V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) and activates AKT(PKB)-dependent signaling pathways.

In multiple cells, binding of PLAU (UPA) to PLAUR (UPAR) activates the Mitogen-activated protein kinase 1-3 (ERK1/2) pathway [8]. After PLAU (UPA) stimulation, integrins associate with FAK1 and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src) kinase. In turn, c-Src activates the Epidermal growth factor receptor (EGFR) that results in the recruitment of the SHC (Src homology 2 domain containing) transforming protein 1 (Shc)/ Growth factor receptor-bound protein 2 (GRB2)/ Son of sevenless homolog (SOS) to the activated receptor, thereby leading to v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) activation. Activated H-Ras activates the v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ ERK1/2 cascade [9]. EGFR serves as a critical adaptor protein in the pathway that links PLAU (UPA) to ERK1/2.

Upon activation of PLAUR (UPAR) by clustering, Janus kinase 1 (JAK1) associates with the receptor, and Signal transducer and activator of transcription 1 (STAT1) is phosphorylated. Then STAT1 dimerizes, translocates from the cytosol to the nucleus, where it binds to a specific DNA sites. JAK1/STAT1 signal transduction pathway including adaptor protein Interleukin 6 signal transducer (gp130) is associated with PLAUR (UPAR) [10].

Several specific inhibitors inactivate PLAU (UPA) on the cell surface. These inhibitors include the PAI-1, the Serpin peptidase inhibitor, clade B (ovalbumin), member 2 (PAI2), the Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2) [11], and the Serpin peptidase inhibitor, clade A (Protein C inhibitor) [12].

References:

1. Stepanova VV, Tkachuk VA
   Urokinase as a multidomain protein and polyfunctional cell regulator. Biochemistry. Biokhimiia 2002 Jan;67(1):109-18
2. Cesarman-Maus G, Hajjar KA
   Molecular mechanisms of fibrinolysis. British journal of haematology 2005 May;129(3):307-21
3. Naldini L, Vigna E, Bardelli A, Follenzi A, Galimi F, Comoglio PM
   Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. The Journal of biological chemistry 1995 Jan 13;270(2):603-11
4. Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM
   Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. The EMBO journal 1992 Dec;11(13):4825-33
5. Li Y, Lawrence DA, Zhang L
   Sequences within domain II of the urokinase receptor critical for differential ligand recognition. The Journal of biological chemistry 2003 Aug 8;278(32):29925-32
6. Stepanova V, Jerke U, Sagach V, Lindschau C, Dietz R, Haller H, Dumler I
   Urokinase-dependent human vascular smooth muscle cell adhesion requires selective vitronectin phosphorylation by ectoprotein kinase CK2. The Journal of biological chemistry 2002 Mar 22;277(12):10265-72
7. Dumler I, Stepanova V, Jerke U, Mayboroda OA, Vogel F, Bouvet P, Tkachuk V, Haller H, Gulba DC
   Urokinase-induced mitogenesis is mediated by casein kinase 2 and nucleolin. Current biology : CB 1999 Dec 16-30;9(24):1468-76
8. Nguyen DH, Hussaini IM, Gonias SL
   Binding of urokinase-type plasminogen activator to its receptor in MCF-7 cells activates extracellular signal-regulated kinase 1 and 2 which is required for increased cellular motility. The Journal of biological chemistry 1998 Apr 3;273(14):8502-7
9. O'Bryan JP, Lambert QT, Der CJ
   The src homology 2 and phosphotyrosine binding domains of the ShcC adaptor protein function as inhibitors of mitogenic signaling by the epidermal growth factor receptor. The Journal of biological chemistry 1998 Aug 7;273(32):20431-7
10. Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR
    Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. The Journal of biological chemistry 1997 Nov 7;272(45):28563-7
11. Kanse SM, Chavakis T, Al-Fakhri N, Hersemeyer K, Monard D, Preissner KT
    Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1. Journal of cell science 2004 Jan 26;117(Pt 3):477-85
12. Meijers JC, Marquart JA, Bertina RM, Bouma BN, Rosendaal FR
    Protein C inhibitor (plasminogen activator inhibitor-3) and the risk of venous thrombosis. British journal of haematology 2002 Aug;118(2):604-9