fak src family of kinases

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FAK/Src family of kinases: Protective oraggravating factor for ischemia reperfusioninjury in nervous system?

ARTICLE in EXPERT OPINION ON THERAPEUTIC TARGETS DECEMBER 2014

Impact Factor: 5.14 DOI: 10.1517/14728222.2014.990374

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5 AUTHORS, INCLUDING:

Christos Bikis

Universittsspital Basel2PUBLICATIONS 12CITATIONS

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Demetrios Moris

Cleveland Clinic91PUBLICATIONS 120CITATIONS

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Ioanna Vasileiou

Hellenic Open University

36PUBLICATIONS 269CITATIONS

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Stamatios Theocharis

National and Kapodistrian University of Athens

275PUBLICATIONS 3,851CITATIONS

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Available from: Demetrios Moris

Retrieved on: 21 January 2016
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1. Introduction

2. Body

3. Conclusion

4. Expert opinion

Review

FAK/Src family of kinases:protective or aggravating factorfor ischemia reperfusion injury in

nervous system?Christos Bikis, Demetrios Moris, Ioanna Vasileiou, Eustratios Patsouris &Stamatios TheocharisNational and Kapodistrian University of Athens, Athens, Greece

Introduction: The focal adhesion kinase (FAK) and the Src families of kinases

are subfamilies of the non-receptor protein tyrosine kinases. FAK activity is

regulated by gene amplification, alternative splicing and phosporylation/

dephosphorylation. FAK/Src complex has been found to participate through

various pathways in neuronal models of ischemia-reperfusion injury (IRI)

with conflicting results. The aim of the present review is to summarize the

currently available data on this subject.Areas covered: The MEDLINE/PubMed database was searched for publications

with the medical subject heading IRI and FAK and/or Src, nervous system. We

restricted our search till 2014. We identified 93 articles that were available in

English as abstracts or/and full-text articles that were deemed appropriate for

our review.

Expert opinion: FAK has been found to have a beneficial preconditioning

effect on IRIthroughactivation viathe protein kinase C (PKC) pathway by anes-

thetic agents. Of great importance are the interactions between FAK/Src and

VEGF that has been already detected as a protective mean for IRI. The effect

of VEGF administrationmightdepend on dose as well as on time of administra-

tion. A Ca2+/calmodulin-dependent protein kinase II or PKC inhibitors seem to

have protective effects on IRI by inhibiting ion channels activation.

Keywords: focal adhesion kinase, ischemia-reperfusion injury, nervous system, Src

Expert Opin. Ther. Targets [Early Online]

1. Introduction

The Focal adhesion kinase (FAK) family of kinases is a subfamily of the non-receptor protein tyrosine kinases (PTKs), counting two members, FAK andFAK2. Src family of kinases (SFK) is another non-receptor PTK subfamily, whichis characterized by morphological similarity to FAKs [1]. Ischemia reperfusion injury(IRI) refers to the damage caused to tissues that have been deprived of blood supply,

after blood circulation is restored. While injury as a result of ischemia (ischemicinjury) seems a relatively easy to deduce consequence, the notion of damage causedby restoring nutrient and oxygen supply--Reperfusion Injury--might at first seemparadoxical. Nevertheless, IRI constitutes a major clinical problem that occurs as anoutcome of diverse situations and can practically affect any tissue or organ. Morespecifically, its effects can vary from subclinical, cellular-level damage to acute vitalorgan deficiency and death. Almost any human cell is susceptible to IRI, whichmakes it easy to propose some common, basic mechanisms of this phenomenon.On the other hand, it still remains difficult to elucidate those mechanisms to theirfull extent for every different cell, tissue and organ, due to the numerous interac-tions that occur when moving from simple in vitroto complexin vivomodels.

10.1517/14728222.2014.990374 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 1

All rights reserved: reproduction in whole or in part not permitted
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The aim of the present review is to elucidate the role ofFAK/SFKs during IRI in the nervous system.

2. Body

2.1 Materials and methods

We performed an electronic search through PubMed/Medlinedatabase by using the key terms: FAK*, Src family*, SFK*,organ*, IRI* and system*. The initial relevant studies retrievedfrom the literature were 249 from PubMed. This number wasinitially limited, after excluding the reviews and studies report-ing data for pathways other than FAK, to number articles.

After going through the manuscripts found from this search,we excluded studies that did not fulfill the criteria--as far as allthe necessary variables or values is concerned--for analysis toour review. The final number of articles included in the reviewabout role of FAK in IRI were 93. Two independent reviewers

(CB and DM) performed the literature search, the study selec-tion and the data extraction. There was no time or publicationlimit in our literature search, whereas allthe references from theidentified articles were also searched for relevant information.

2.2 General principles

2.2.1 The FAK family of kinases

FAK is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normaland diseased cells through its kinase activity and scaffoldingfunction [1,2]. Although it was originally characterized as a

constituent of focal adhesions in fibroblasts, FAK is now con-sidered to be not only a mediator of adhesion processes butalso a crucial regulator of guidance and a modulator of geneexpression [3].

FAK is the main transducer of the integrin signalingrequired to stabilize the actin cytoskeleton. Moreover, its sig-

naling involves not only phosphorylation but also ubiquitina-tion and proteolysis [3].

It is the first member of the family of FAK kinases to bediscovered, first described in 1992 [4], and it is located at thefocal adhesion sites (FAS) that play a predominant role in sta-bilizing endothelial cells at the extracellular matrix (ECM) [5].

Although the FAK cDNA codes for a protein of119 -- 121 kDa depending on different species, it is knownas p125FAK, as if it had a molecular weight of 125 kDa, aname which is based on its gel migration signature. FAK,which is an evolutionary conserved protein, has been mappedon the human chromosome 8 and is expressed in a wide vari-ety of cells, with the degree of its expression ranging consider-

ably [5]. The structure of FAK is unique among PTKs incomprising of a central kinase domain flanked by two largenon-catalytic sections, the NH2-terminal region and theCOOH-terminal region, while at the same time having noSH2 or SH3 binding domains, unlike other PTKs [5]. Itdoes have SH2 and SH3-domain interacting phosphotyro-sines and proline-rich regions, respectively, allowing it to acti-vate with the downstream binding molecules [5]. FAK isessential to integrin signaling and once activated by integrinor non-integrin stimuli, such as cell adhesion and stimulationby growth factors, it binds to a series of molecules activatingthem and initiating a series of signaling pathways. The mostprominent integrin, whose action is associated with FAK, isb1-integrin, but FAK can also be activated by b3 andb5 integrins [6]. Integrin activation and clustering leads tothe binding of FAK to the cytoplasmic domain of activatedb1-integrins and its subsequent autophosphorylation on tyro-sine residue Y397, creating a special binding site for theSH2 domain of the SFKs [6-8]. After binding to FAK, Srcphosphorylates the first at several domains, including tyrosineresidues Y576/Y577 and Y861 further increasing its activityas a kinase [ 7]. The formation of this bipartite complex resultsin the enzymatic activation of both kinases, which in turn canact on and interact with a number of molecules [7,9]. The down-stream molecules activated by the FAK-Src complex through

phosphorylation include p130Cas (a docking protein), growthfactor receptor-bound protein-2, phosphoinositide-3 kinase(PI3K) and paxillin (a cytoskeletal/adapter protein) [9,10].

The other member of the FAK family of kinases, namedFAK2, or PYK2 (proline-rich tyrosine kinase 2), or cell adhe-sion kinase, is a 116 kDa cytoplasmic kinase highly expressedin the CNS, which has been shown to follow the same basicprinciples with FAK. PYK2 activation results from its auto-phosphorylation on Tyr-402, thus creating an SFK bindingsite and creating the FAK2/Src complex, whose mechanismof action is similar to the aforementioned FAK/Src complex.

Article highlights.

. Ischemia-reperfusion injury (IRI) constitutes a majorclinical problem affecting any tissue or organ but it stillremains difficult to elucidate those mechanisms involvedto its development to their full extent for every different

cell, tissue and organ.. Focal adhesion kinase (FAK)/Src complex activity has a

crucial role in cell--extracellular matrix interaction andthe transduction of extracellular signals and thusregulating cellular behaviors such as migration,proliferation and differentiation.

. FAK is essential to integrin signaling and once activatedby integrin or non-integrin stimuli, such as cell adhesionand stimulation by growth factors, binds to a series ofmolecules activating them and initiating a series ofsignaling pathways.

. The most prominent integrin, whose action is associatedwith FAK, is b1-integrin.

. The FAK family of kinases in the pathogenesis of IRI isprobably biphasic and complex, since they may take part

in a series of a series of pathways that may at first seemto have opposing actions.. A number of anesthetic agents such as anandamide,

thiopental, isoflurane and sevoflurane activate FAK viathe PKC pathway and thus have a beneficialpreconditioning effect on IRI.

This box summarizes key points contained in the article.

C. Bikis et al.

2 Expert Opin. Ther. Targets (2014) 19 (4)
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Under normal circumstances, FAK activity is carefully reg-ulated by gene amplification, alternative splicing and phos-porylation/dephosphorylation. Moreover, due to its locationand its affinity with integrins, FAK/Src complex activity playsa predominant role in cell-ECM interaction as well as thetransduction of extracellular signals across the plasma mem-

brane, regulating cellular behaviors such as migration, prolif-eration and differentiation [6,10]. The importance of thisdelicate balance of mechanisms that exists in normal cells isevident in the case of oncogenesis [4]. Tumor cells are charac-terized by disrupted, inhibited or unchecked FAK signalingwhich promotes malignant characteristics, such as overprolif-erating, antiapoptotic, invasive adhesive and migrating quali-ties, coupled with tumor angiogenesis and metastasisabilities [2,4,10,11]. The contradictory remarks that both FAKinduction or inhibition can result in malignant phenotypesfurther prove that FAK/Src activation is the first step in aseries of signaling pathways that regulate a considerable num-ber of widely diverse cellular functions. Another field where

the data on FAK action are controverisal is the aspect of cyto-toxicity. While cytotoxic substances such as arsenic (As), lead(Pb), acrylamide, methylisothiazolinone, dichlorovinylcys-teine and halothane have been proven to exert their actionat least partially through downregulation of FAK phosphory-lation [12,13], the bacterial toxins Pasteurella multocida toxinand Escherichia coli cytotoxic necrotizing factor have beenshown to induce cytotoxicity by the exact opposite mecha-nism, namely the increased FAK phosphorylation. an andb1 integrins mediate Ab-induced neurotoxicity in primaryhippocampal neurons by causing Ab-induced apoptosis [14].The underlying pathogenesis may be related to activation oftyrosine-phosphorylation by FAK[14]. Inhibition of the inter-action between Aband Itgs or the interruption of FAK activa-tion may effectively inhibit apoptosis in hippocampal neuronsin diseases such as Alzheimers disease (AD) pathogenesis [14].

2.2.2 Ischemia reperfusion injury

IRI refers to the damage caused to tissues that have beendeprived of blood supply, after blood circulation is restored.

As we have already mentioned, IRI can be caused by a varietyof conditions with a variety of presentations and affect any tis-sue or organ. Adding to the complexity of the matter at hand,IRI is considered to be able to activate both apoptotic andanti-apoptotic or proliferating, invading and migrating path-

ways, alternatively or at once, with the end result dependingon a number of factors that remain to be clarified.A series of hypotheses have been given concerning the path-

ogenesis of IRI, ranging from the dysfunction of the mito-chondrial system and the mobilization of calcium and thedepletion of ATP at cellular level, to the disruption of celladhesion and cytoskeletal network at tissue level.

At cellular level, oxidative stress plays the pivotal role inIRI. The creation of reactive oxygen species (ROS) after thereperfusion and re-oxygenation of a formerly ischemic tissuehas been already proven in brain cell models [11,13,15,16]. Three

main sources of ROS during IRI exist: i) the mitochondrialrespiratory complex, mainly in non-phagocytic cells [16,17];ii) the (Nicotinamide adenine dinucleotide phosphate oxi-dase)-Nox family of oxidases [15,18]; and iii) other sources,such as the neutrophil-specific myeloperoxidase and the-present in the liver-xanthine oxidase enzymes [17-20]. After

the onset of ischemia, as well as following reperfusion, a seriesof signaling pathways are set in motion, with the family ofMAPK having already been recognized as mediators ofsignificant importance [20,21].

Apart from the production of ROS at cellular level, theimmune system seems to be a contributing factor to IRI at tis-sue level, as far as cell adhesion is concerned. It seems logicalto assume that the compromised cytoskeletal network integ-rity and the disrupted cell adhesion observed in IRI can onlybe explained by a multi-factor model, including a potentiallylarge number of the proteins clustered at FAS. The ATPdepletion observed in IRI, serves as a further argument tothis case, because ATP-dependent protein phosphorylation

is one of the principal regulatory mechanisms in the-richwith protein complexes-FAS.

2.2.3 Role of FAK in IRI

The seemingly bipolar action of the FAK/Src complex is alsoevident in the case of IRI (Figure 1). It has already been proventhat the increased adhesion of polymorphonuclear neutrophilsto endothelial cells, following the production of ROS coin-cides with the increased phosphorylation of several proteinslocated at the FAS, such as the cytoskeletal proteins paxillinand p130 cas, as well as several tyrosine kinases, which havebeen identified as members of the FAK/Src family [9,19]. Onthe other hand, while increased ROS production leads toincreased FAK production, ischemia by itself causes FAKcleavage and depletion from FAS, leading to the conclusionthat the involvement of the FAK family of kinases in the path-ogenesis of IRI is probably biphasic and complex, since theymay take part in a series of pathways that may at first seemto have opposing actions [21]. Furthermore, the reaction ofthe FAK/Src complex during IRI can vary significantlybetween different systems of the human organism and evenin different parts and tissues of the same organ, rendering amore detailed and individualized approach necessary.

2.3 Nervous system and IRI

The role of FAK/Src in neuronal models of IRI has been theobject of considerable research, which in some cases leads toconsistent results and in others, at least primarily, and contra-dicting observations. It should also be pointed out expresslythat FAK and its similar PYK2 interact differently with eachtype of neuronal cells [21,22]. It is easier thus to observe theseinteractions separately as far as that is possible.

Normally, the FAK/Src complex has been found to workthrough a series of pathways, one of which most probablyincludes the association with p130Cas, with the activationof extracellular-signal-regulated kinases (ERK) through the

FAK/Src family of kinases: protective or aggravating factor for ischemia reperfusion injury in nervous system?

Expert Opin. Ther. Targets (2014) 19 (4) 3
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Fyn tyrosine kinase, an effect that finally promotes cellviability [22-24]. Promotion of cell survival was also found tobe triggered by the cells attachment to ECM components,leading to engagement of the integrins and FAK phosphoryla-tion, which would then regulate the interaction of cytoskele-ton actin-bound with the neuronal membrane and alsofunction through the PI3K kinase/Akt and Akt/NF-kB path-

way promoting cell survival [ 24-29]. FAK activity,in vitro, wasalso found to be regulated by signals initiated by growth fac-tor/cytokine receptors and a number of G-protein-coupledreceptors [30-32]. Table 1summarizes the role of FAK in IRI.

The importance of FAK/Src system for cell signaling isprominent through the modifications induced by diversepharmaceutical substances. Various extracellular signals thatincrease the intracellular Ca2+ lead to the protein kinase C(PKC) family activation and thus, the stimulation of FAKvia phosphorylation [25]. However, while a number of anes-thetic agents such as anandamide, thiopental, isoflurane and

sevoflurane activate FAK via the PKC pathway and thushave a beneficial preconditioning effect on IRI [33-35], anotherFAK phosphorylation pathway exists, with activation of thea2-adrenoceptor adenylate cyclase pathway, as it was observedin the case of canabinoid 1 (CB1) receptors which are nega-tively coupled to adenylate cyclate [36-38] and the beneficial

preconditioning effect of dexmedetomidine, which activatesthe a2-adrenoceptor-adenylate cylcase pathway, in IRI mod-els [39]. Recently, Dalton et al. [38]showed that CB1receptoragonists failed to stimulate FAK Tyr-P in the absence of integ-rin activation in neuronal cells. In contrast, in integrin pres-ence, ligands such as fibronectin and laminin displayedincreased FAK 576/577 Tyr-P that was augmented by CB1receptor agonists and blocked by the Src inhibitor PP2 andFlk-1 VEGFR antagonist SU5416 (Table 2) [38].

On the most classic IRI model, that of ischemia caused byshort-time selective vessel occlusion, followed by reperfusion,some of the observed results are the decrease of FAK Tyr-397phosphorylation (after 24 --72 h, probably initiated by ATP

depletion), the decrease of the FAK/Src interaction complex,the decrease of the total amount of FAK, the decrease of lam-inin levels and the increased MMP activity, while there is noeffect on the FAK/p130Cas complex and the MMP expres-sion [40,41]. The degradation of ECM proteins such as lamininalters and disrupts the cell adhesion to the ECM, thus leadingto a decrease of the FAK phosphorylation and a subsequentdecreased FAK/Src association, a prelude to cellular apopto-sis [40,42]. Furthermore, the decrease of the total amount ofFAK could be up to a part caused by the overactivation of cal-pain and caspaces, a finding on non-neuronal cells that is pos-sible to additionally apply to neuronal ones [43-47]. One otherequivalent IRI model is that of chemical insult, which hasbeen found to lead to generation of ROS, activation of phos-photyrosine phosphatases and subsequent inhibition of SFKsby disassembly, inhibition and degradation of FAK, as wellas disassembly of the FAK/Src complex [48].

On the other hand, some upstream or downstream effectsof IRI and FAK/Src deserve more attention than others suchis the case with VEGF. In normal conditions, interactionbetween VEGF and integrin avb3 leads to FAK phosphoryla-tion, which according to what has been already mentionedwould mean that upregulation of VEGF serves as a protectivemean for IRI [49-51]. On the other hand, things are more com-plicated than they seem. Studies that reveal favorable effects of

blocking VEGF before IRI [52,53], show that the mechanism ismore complex and other parameters should also be taken intoaccount. During IRI, treatment with the VEGF inhibitorcyclo[Arg-Gly-Asp-D-Phe-Vall] (cRGDFV), resulted in adecrease in the inflammatory cells recruitment and also to adecreased FAK phosphorylation, possibly due to the blockingof the interaction between the integrin avb3 (upregulatedselectively after brain ischemic injury) and the peptidesequence argine-glycine-aspartic acid (RGD) [54,55], an eventthat could obstruct FAK/integrin association and thus thephosphorylation of the former. As an end result of cRGDFV

ROSIntracellular Ca2/PKC

ECM/integrins

VEGF

FAK

Src

Cell differentiation

Nedd9 gene

Cytoskeletalproteins

p130 cas,paxillin

Cell survival

PI3K/Akt

MARK

ERK/Fyn tyrosinekinase

Akt/NF-kB

Figure 1. An illustration of the role of the FAK/Src complex

in the case of ischemia reperfusion injury.ECM: Extracellular matrix; FAK: Focal adhesion kinase; Nedd9: Neural precur-

sor cell expressed, developmentally down-regulated 9; PI3K: Phosphoinositide-

3 kinase; PKC: Protein kinase C; ROS: Reactive oxygen species.

C. Bikis et al.

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administration, focal cerebral ischemic damage was amelio-rated [56]. It was also shown that the mechanism of VEGFfrom recruited inflammatory cells, promoted survival insteadof apoptosis, as would have been expected from the FAKdephosphorylation result alone. To that avail, the protectiveeffects of soluble flt-1 gene transfer, a natural VEGF inhibitor

are of interest [57]. Last but not least, one should also take intoaccount the fact that during ischemia, VEGF interacts directlywith Src, increasing vascular permeability and thus aggravat-ing the ischemic damage [58]. Therefore, blockade of Srcreduces neuronal damage after brain ischemia [59]. To sumup, it seems that during ischemia, VEGF interaction leadsto acute angiogenesis, FAK phosphorylation and also activa-tion of other, contradicting damage inducing mechanisms.

As a result, VEGF administration after ischemia can eitherreduce or cause more damage depending on both concentra-tion and time of administration. Up to now, it seems that in

the early phase of IRI is better to block VEGF rather thanupregulate it.

Another interesting observation, that correlates the FAK/Src pathway not only with cell survival but also with neuronaldifferentiation is the observed effect of the neural precursorcell expressed, developmentally down-regulated 9 (Nedd9)

gene on FAK/Src. Nedd9, a splicing variant of Cas-L (Crk-associated substrate lymphocyte-type) plays a role in neuronaldifferentiation that is normally not existent in the adultbrain[8,60,61]. The Cas-L protein interacts and gets phoshpory-lated by both FAK and PYK2[ 62], with IRI causing increasedexpression of both Nedd9 mRNA and FAK, as well asincreased interaction between them [8]. As a result, after ische-mia, Nedd9/FAK delayed expression was found to contributeto neuronal damage repair [8,63]. The effect of Nedd99 revealsthe possible role that FAK/Src plays in neuronal differentia-tion. Although of the postnatal age has no effect on the

Table 1. Summary of the role of FAK in ischemia-reperfusion injury.

Author Year Study design Mechanism of action Result Model

Schlaepfer et al. [22] 1998 Experimentalstudy

FAK/Src complex work throughp130Cas and with the activationof ERK through the Fyn tyrosine

kinase

Promotes cellviability

Integrin stimulation byfibronectin leads to changes inintracellular protein tyrosine

phosphorylation eventsIgishi et al. [24] 1999 Experimental

studyActivated FAK stimulated ERKand JNK activity by inducingtyrosine phosphorylation of Shc

Cell stimulation Fibronectin was used as atrigger to FAK activation. FAK tostimulate signaling eventsleading to the activation of ERKand JNK

Linet al. [23] 2004 Experimentalstudy

FAK binds to the b1 integrincytoplasmic domain, andsubsequently binds to the SH2domain of c-Src, as well asp130cas

Cell spreading,motility andproliferation

Following integrin occupancy,FAK is autophosphorylated atY397, thereby creating abinding site for the SH2 domainof c-Src family kinases. Thec-Src/FAK complex stabilizesc-Src catalytic activity. Activatedc-Src then phosphorylatesadditional sites on FAK,

including the regulatory looptyrosines, Y576 and Y577, inthe catalytic domain, therebyenhancing FAK activity

King et al. [29] 1997 Experimentalstudy

The association of (PI) 3-kinasewith FAK was induced by theattachment of fibroblasts tofibronectin and was dependenton the SH2 domain of p85

Cell spreading,motility andproliferation

Cell attachment to fibronectinstimulates the integrin-dependent interaction ofp85-associated PI 3-kinase withintegrin-dependent FAK as wellas activation of the Ras/mitogen-activated protein kinasepathway

Tamura et al. [28] 1999 Experimentalstudy

Cells attachment toextracellular matrix components,leads to engagement of theintegrins and FAKphosphorylation

Promotion ofcell survival

The interaction of cytoskeletonwith the neuronal membraneand also function through thephosphoinositide-3 kinase/Aktand Akt/NF-kB pathwaypromotes cell survival

ERK: Extracellular-signal-regulated kinases; FAK: Focal adhesion kinase; PI: Phosphatidylinositol.


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Table 2. Summary of the studies referring to therapeutic interventions aimed to target FAK.

Author Year Study design Intervention Mechanism of action Results

Derkinderen

et al.[35]

1996 Experimentalstudy

Anandamide Anandamide is anendogenous ligand forcannabinoid receptors. Itincreases protein tyrosinephosphorylation in neurons.One of the proteinsphosphorylated is FAK+expressed preferentially inneurons

The activation FAK via thePKC pathway has abeneficial preconditioningeffect on IRI

Dahmaniet al. [34]


Thiopental and isoflurane Oxygen-glucose deprivationdecreases the ATP-dependent phosphorylationprocess of Focal AdhesionKinase (pp125FAK)

Phosphorylated pp125FAKcontent was markedlydecreased in neuronal tissuesubjected to oxygen-glucosedeprivation. Thiopental andisoflurane significantlyattenuated thisphenomenon, possibly via

PKC activationDahmaniet al. [37]


Thiopental, propofol,etomidate, isoflurane,sevoflurane and desflurane(anesthetic agents)

The anesthetic-inducedincrease in ppFAKphosphorylation was blockedby three structurally distinctinhibitors of PKC. g-aminobutyric acid type Areceptor antagonist andinhibitor of the ryanodinereceptor were ineffective inblocking anesthetic-inducedactivation of tyrosinephosphorylation

Anesthetic agents markedlyincrease tyrosinephosphorylation of ppFAK inmost likely via thephospholipase C-PKCpathway

Dahmaniet al. [39]


Dexmedetomidine onphospho-tyrosine FAK

phosphorylation

Dexmedetomidine is a potentand selective

a2-adrenoceptor agonistthat exhibits a broad patternof actions, includingsedation, analgesia andneuroprotection

Increase in phosphorylationof FAK via stimulation of a2

adrenoceptors and decreasein cleaved caspase-3expression correlate withdexmedetomidine-inducedcell survival

Burnettet al. [54]Nisatoet al. [55]

2005

2003

Experimentalstudy

cyclo[Arg-Gly-Asp-D-Phe-Vall](cRGDFV-VEGF inhibitor)

In normal conditions,interaction between VEGFand integrin avb3 leads toFAK phosphorylation, whichmeans that upregulation ofVEGF acts protectively in IRI

Decrease in the inflammatorycells recruitment leads to adecreased FAKphosphorylation, possiblydue to the blocking of theinteraction between theintegrin avb3

Liu Yet al. [69]Liu Yet al. [70,71]

2001

2003

Experimentalstudy

Ketamine (NMDA receptorselective antagonist) andNifedipine (the L-voltagegated Ca2+ channelantagonist)

Glutamate as well as cellmembrane depolarizationhave been shown to increaseSrc activation and thusfurther increase the PYK2/Srcinteraction, which is alsofacilitated by thetranslocation of PKC, Src,Fyn and Pyk2 to postsynapticdensity protein postischemia

The end result is theactivation of PYK2 by twoindependent pathways dueto calcium influx, a PKCdependent one and a Ca2+/CaM and CaMKII dependentone, independent to eachother. KN62 (a CaMKIIinhibitor) or CHE (a selectivePKC inhibitor) will have agreater protective effect thanNifedipine or Ketamine alone

CaM: Calmodulin; CaMKII: Ca2+/calmodulin-dependent protein kinase II; FAK: Focal adhesion kinase; IRI: Ischemia-reperfusion injury; PKC: Protein kinase C;

PYK: Proline-rich tyrosine kinase.

C. Bikis et al.

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amount of FAK and p130Cas, Src was found to increase withmaturation by Zalewska et al. [64]. In the same frame, thesame research team [40] revealed a very interesting temporalbiphasic pattern with regard to FAK/Src activity after IRI.

After its onset, IRI leads to activation of the energy-dependent ion channels resulting in loss of the membrane

potential. Cell depolarization is then the trigger for the activa-tion of voltage gated Ca2+ channels (VGCC), as well as thecause of neurotransmitters release (e.g., excitatory aminoa-cids) which then accumulate in the synapse and lead to activa-tion of ligand-gated calcium channels, with the characteristicexample of NMDA [65-67]. The openness of both types ofchannels, leads to the aforementioned influx of Ca2+, whichhas a dual effect. First, it leads to the activation of PYK2 ina PKC-dependent manner and the subsequent PYK2/Srccomplex formation. Second, it acts as the onset of furthercalcium-dependent signaling cascades which cause an earlyefflux of glutamate, which further activates the NMDA recep-tors, creating a positive feedback circuit [68]. Furthermore,

glutamate as well as cell membrane depolarization have beenshown to increase Src activation and thus further increasethe PYK2/Src interaction, which is also facilitated by thetranslocation of PKC, Src, Fyn and Pyk2 to postsynapticdensity protein (PSD) postischemia [69-75].

That can also been proven by observing the effect of Keta-mine (NMDA receptor selective antagonist) and Nifedipine(L-VGCC antagonist) have on PYK2 activation, also suggest-ing a possible cross-talk between the NMDA and theL-VGCC channels by returning back through the proposedclosed loop [69,76,77]. The end result is the activation ofPYK2 by two independent pathways due to calcium influx,a PKC-dependent one and a Ca2+/Calmodulin (CaM) andCaM-dependent protein kinase II (CaMKII) dependent one,independent to each other [77].

It is also noteworthy to point out that the later on we targetthe described pathway with an inhibitor, the greater will thepercentage of final loss of PYK2 activity will be, that is,KN62 (a CaMKII inhibitor) or CHE (a selective PKC inhib-itor) will have a greater protective effect than Nifedipine orKetamine alone.

Interestingly, CHE also has another blocking capability,namely preventing the Src-induced phosphorylation ofNMDA receptor subunit 2A (NR2A), NR2B which wouldcause our positive feedback circuit that was mentioned above,

also indicating PKC involvement in the NR2A, NR2B phos-phorylation [78]. Last but not least, it should be noted thatalthough this mechanism generally holds true at a structurallevel, the different times of activation for individual pathwayscould vary in different cells tissue types, therefore explainingthe following finding of Liu et al. [71] who referred that 1 hafter the onset of focal cerebral ischemia, PYK2 activity wasobserved mainly in the cortical neurons, whereas after24--72 h PYK2 was mostly evident in microglia around theinfracted area, suggesting a second-step microglia activationas part of the recovery/death mechanism.

The consequences of the aforementioned cascade web indetail are as follows: First of all, the activated PYK2 andPSD-95 lead to Src activation and the onset of the Src-MAPKsignaling pathway which promotes cell apoptosis [69,78-84].These apoptotic-leading MAPK pathways, which requireG-protein-coupled receptors, include the p38 MAPK pathway,

the c-Jun-N-terminalkinase pathway andthe ERK pathway[85].Especially, as far as the ERK is concerned, there seems to be

a need for more research, since Corvol et al. [86] noted thatPYK2 and ERK were activated at different cellular compart-ments after KCl depolarization of Hippocampal slices,although that finding could also be attributed to the method-ological differences of using KCl depolarization instead of theclassical IRI model and hippocampal tissue slices instead ofcell lines. In any case, it is important to consider the differen-ces that arise between different cell types in a certain tissueand homogenous cell series.

It was also demonstrated that autophosphorylation ofPYK2 was dramatically decreased in fun -/- mice but unal-

tered by SFK inhibitors, suggesting that in the proposedmodel, Fyn plays a role in the control of PYK2, not limitedto its, already known, catalytic activity.

Apart from the Src/MAPK pathway activation, the acti-vated PYK2/Src complex also performed NMDAR additionalphosphorylation, both at NR2A and NR2B [84,87], mediatedthrough the interaction with the PSD-95 protein [84,88].

PSD-95-mediated tyrosine phosphorylation of L-VGCCa1C subunits [ 89]as well as NMDAR additional phosphoryla-tion lead to delayed neuronal death due to a vicious circle ofCa2+ influx.

Finally, PSD-95-mediated downstream calcium-dependentnitric oxide production [77]may lead to ischemic and excitoxicneurodegeneration.

At this point, apart from the various targeted inhibitors thatare quite obvious by considering the described pathways, aspecial reference should be made with regard to lithium,which yields a multiple protective effect against the PYK2/Src complex activation.

First, it suppressed the PYK2/PSD95 interaction necessaryfor NMDAR additional phosphorylation. Second, it sup-pressed the NR2A/PYK2 interaction and the NR2A, NR2Bphosphorylation also involved in NMDAR additional phos-phorylation. And finally, it caused a decrease in the phosphor-ylation of both PYK2 and Src, thus limiting the total complex

activity in general.

3. Conclusion

Current data on FAK/Src and IRI remain limited, but clearlyindicate the contradicting actions of FAK/Src in neuronalcells. The FAK family of kinases in the pathogenesis of IRIis probably biphasic and complex, since they may take partin a series of a series of pathways that may at first seem tohave opposing actions. Anesthetic agents activate FAK viathe PKC pathway and thus have a beneficial preconditioning


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effect on IRI. Nevertheless, further investigation is required inorder to establish their possible contribution in humanneuronal IRI.

4. Expert opinion

It was clearly shown that FAK exerted a beneficial precondi-tioning effect on IRI through activation via the PKC pathway(e.g., anesthetic agents). Regarding the most common modelof neuronal IRI, that induced by vessel occlusion, decreasedFAK phosphorylation and a decrease in FAK/Src associationleads to cellular apoptosis. Of great importance are the interac-tions between FAK/Src and VEGF that have been alreadydetected as a protective mean for IRI. However, studies in neu-ronal IRI reveal favorable effects of blocking VEGF before IRI,via obstruction of FAK phosphorylation. It could be thus sug-gested that the administration of a VEGF-inhibitor could ame-liorate the focal cerebral ischemia damage. Moreover, blockadeof Src reduces neuronal damage after brain ischemia. Other

studies, however, exist, which promote the protective role ofVEGF in IRI. The results of VEGF administration mightthus depend on concentration as well as on time of administra-tion. PYK2/Src complex has also been found to induce apopto-sis in non-neuronal cells after its activation. Regardingneuronal cells, a CaMKII or a PKC inhibitor seem to have pro-tective effects on IRIby inhibiting ion channels activation. Fur-thermore, lithium seems to exert a protective effect on IRI bydecreasing phosphorylation of PYK2 and Src.

Moreover, as we have already presented [90], proteasomesmodification could be an effective future therapeutic strategyfor neuronal IRI due to its correlation with pathways suchas NF-kB inactivation and the cytoprotective proteins endo-thelial nitric oxide synthase, whose role, in the IRI in neuronalcells, was described in this review article.

In recent years, FAK has also been strongly implicated as acrucial regulator of insulin resistance in peripheral tissues likeskeletal muscle and liver, where decrease in its expression/activity has been shown to lead to insulin resistance [91]. Inneurons, FAK acts as a negative regulator of insulin/PI3K sig-naling [92]. FAK, which is well known for its cell survival

effects, has been shown to be involved in neurodegenera-tion [93]. These findings highlight a novel and critical role ofFAK in neurons. Furthermore, as this implicates differentialregulation of insulin/PI3K pathway by FAK in peripheral tis-sues and neuronal cells, it strongly suggests precaution whileconsidering FAK modulators as possible therapeutics.

Finally, the study of Han et al. [14] showed that an andb1 integrins mediate Ab-induced neurotoxicity in primary hip-pocampal neurons by activating of tyrosine-phosphorylationby FAK. This can stand as a potential mechanism for AD path-ogenesis. Thus, this study may provide insight towards thedevelopment of novel AD treatments.

Acknowledgement

C Bikis and D Moris contributed equally to this work.

Declaration of interest

The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testi-mony, grants or patents received or pending, or royalties. Thisresearch received no specific grant from any funding agency inthe public, commercial, or not-for-profit sectors.

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