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Immune response Role of integrins in NK cells cytotoxicity


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Immune response Role of integrins in NK cells cytotoxicity

Role of integrins in NK cells cytotoxicity

Natural killer (NK) cells are lymphocytes of innate immune system. They recognize andkill aberrant cells without immunization or pre-activation, by releasing cytotoxicgranules and rapidly produce soluble factors - chemokines and cytokines. NK cells featurea variety of cell surface receptors, and their engagement determines whether NK cellswill attack target cells [1], [2].

Integrin receptors are adhesion receptors involved in NK cells migration, adhesion ofNK cell to target cell and the follow-up cytotoxicity. This map displays signaling ofthree adhesion receptors - alpha-L/beta-2 integrin, alpha-M/beta-2integrin and alpha-4/beta-1 integrin.

The common ligand for alpha-L/beta-2integrin and alpha-M/beta-2integrinis Intercellular adhesion molecule 1 ( ICAM1 ) [3], [4].In addition, alpha-L/beta-2 integrin binds Intercellular adhesion molecule 2 (ICAM2 ) [5] and Intercellular adhesion molecule 3 ( ICAM3 )[6]. Fibronectin [7] and Vascular cell adhesion molecule1 ( VCAM1 ) [4], [8] are the ligands foralpha-4/beta-1 integrin cells.

Ligand-receptor binding leads to activation of PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2) ) [9], [10], [4]. Activation ofPyk2(FAK2) from integrins is probably realized via Guanine nucleotide bindingprotein beta polypeptide 2-like 1 ( RACK1 )/ Protein kinase C, epsilon (PKC-epsilon) pathway [11]. 

Alpha-4/beta-1 integrin - and/or alpha-L/beta-2 integrin -activatedPyk2(FAK2) are associated with Vav 1 guanine nucleotide exchange factor (VAV-1 ), which undergoes tyrosine phosphorylation upon integrin triggering (e.g.,via FYN oncogene related to SRC, FGR, YES ( Fyn ) [12], [13] ). The phosphorylated VAV-1 activates ras-related C3 botulinum toxinsubstrate 1 ( RAC1 )/ p21 protein (Cdc42/Rac)-activated kinase 1 ( PAK1 )cascade . Signals from PAK1 lead to cytoskeleton rearrangement, formation of a stablelamellipodium and following transendothelial migration NK cells to target cells [4], [14].

Then a NK cell finds and binds to the surface of target cells.

Alpha-L/beta-2 integrin and alpha-4/beta-1 integrin participate in NKcells adhesion to targets via Paxillin and Pyk2(FAK2) [15]. Theexact mechanism of adhesion is unknown [16], [17].

In addition, Alpha-L/beta-2 integrin and alpha-4/beta-1 integrinparticipate in cytotoxicity of NK cells [18], [6].

Ligand-receptor binding leads to activation M itogen-activated protein kinases 3 and 1( ERK1 and ERK2, accordingly), probably, via Pyk2(FAK2)/ Srchomology 2 domain-containing transforming protein 1 ( Shc )/ Growth factorreceptor-bound protein 2 ( GRB2 ) interactions. GRB2 activates positiveregulator of Son of sevenless homolog ( SOS ), which results in activation ofv-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras)/ v-raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinasekinases 1 and 2 ( MEK1(MAP2K1) MEK2(MAP2K2) )/ Mitogen activated protein kinases1-3 ( ERK1/2 ) pathway [18].

Activation of ICAM-2 (and/or ICAM-3 )/ Alpha-L/beta-2 integrin-dependent ERK1/2 leads to mobilization of lytic granules with perforin andgranzyme B [6].

In addition, alpha-4/beta-1 integrin and alpha-L/beta-2 integrin mayactivate transcription of certain cytokines which participate in NK cell cytotoxicity[18], [19], [20]. 

Activation of Fibronectin/ alpha-4/beta-1 integrin -dependentERK1/2 leads to stimulation of Interferon gamma ( IFN-famma )transcription, probably, via v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos ), Activating transcription factor 2 ( ATF-2 ) or other [18]. Moreover, alpha-4/beta-1 integrin may activate Pyk2(FAK2)/ras-related C3 botulinum toxin substrate 1 RAC1/ PAK1/ Mitogen-activatedprotein kinase kinase kinase 1 ( MEKK1(MAP3K1) )/ M itogen-activated proteinkinase kinase 3 ( MEK3(MAP2K3) )/ M itogen-activated protein kinases 11-14 (p38MAPK) cascade. p38MAPK, in turn, increases transcription of Interleukin8 ( IL-8 ), possibly, via c-Fos [19].

Alpha-L/beta-2 integrin may activate transcription of FasL via an unknownpathway [21], [20]. Inhibitory receptors block signals from activating receptors with theaid of help attraction of phosphatase and following dephosphorylation of signalingproteins which proceed from activating receptors. Two phosphatases bind to ligand-boundinhibitory receptors Protein tyrosine phosphatases, non-receptor type 6 ( SHP-1 )and 11 ( SHP-2 ) [22], [23].

During Alpha-L/beta-2 integrin-dependent activation of Fas ligand (FasL) transcription is inhibited by Killer cell lectin-like receptor subfamily C,member 1 ( NKG2A )/ Killer cell lectin-like receptor subfamily D, member 1 (CD94 ) [20].