Cell adhesion PLAU signaling

PLAU signaling

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

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

The PLAU (UPA) is an important component of the extracellular protease systembecause 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 ofgrowth factors, e.g. Hepatocyte growth factor ( HGF ) [3], [4]. Growth factors bind to their receptors on the cell surface and activateintracellular signaling pathways that regulate the cell behavior. HGF activatesPhosphatidylinositol-3-kinase ( PI3K ) and V-akt murine thymoma viral oncogenehomolog 1 ( AKT(PKB) ) signaling pathways via adaptor protein GRB2-associatedbinding protein 1 ( GAB1 ).

PLAUR (UPAR) is also a high-affinity receptor for the extracellular matrixprotein Vitronectin. Vitronectin binds to alpha-8/beta-1 integrinand 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 peptidaseinhibitor, 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, betapolypeptide ( Casein kinase II, beta chain (Phosvitin) ) that form an activecomplex with Casein kinase 2, alpha ( Casein kinase II, alpha chains ). Cellsurface-located Casein kinase II is capable of phosphorylating ofVitronectin. Vitronectin is selectively phosphorylated by Casein kinaseII in a PLAU (UPA)/PLAUR (UPAR) -dependent manner and phosphorylatedVitronectin is a better ligand for integrins and PLAUR (UPAR) [6]. PLAUR (UPAR) and Casein kinase II form a functional complex withthe shuttle protein Nucleolin. Nucleolin is an abundant nuclearphosphoprotein that shuttles between the nucleus and cytoplasm and can translocate to thecell surface. PLAU (UPA) can induce cell proliferation through the activation ofthe complex that includes PLAUR (UPAR), Casein kinase II andNucleolin [7].

PLAU (UPA) activates a number of signaling pathways that regulate cytoskeletonremodeling. On the cell surface, PLAU (UPA) binds to the high affinity receptorPLAUR (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)-integrinfamily, and with beta(1)- and beta(3)-integrins. Binding of PLAUR (UPAR) withalpha-8/beta-1 integrin resulted 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 homolog1 ( AKT(PKB) ) and activates AKT(PKB) dependent signaling pathways.

In multiple cells, binding of PLAU (UPA) to PLAUR (UPAR) activates theMitogen-activated protein kinase 1-3 ( ERK1/2 ) pathway [8]. AfterPLAU (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 resultsin the recruitment of the SHC (Src homology 2 domain containing) transforming protein 1 (Shc )/ Growth factor receptor-bound protein 2 ( GRB2 )/ Son of sevenlesshomolog ( SOS ) to the activated receptor, thereby leading to v-Ha-ras Harvey ratsarcoma viral oncogene homolog ( H-Ras ) activation. Activated H-RASactivates the v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ERK1/2 cascade [9].

Several specific inhibitors inactivate PLAU (UPA) on the cell surface. Theseinhibitors 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 ) [10],and the Serpin peptidase inhibitor, clade A ( Protein C inhibitor ) [11].

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