Mutual cross-talk between fibronectin integrins and the EGF receptor: Molecular basis and biological significance.

2012·4.3 MB·English

by  Balanis, Nikolas

CellularLogistics2:1,46–51;January/February/March2012;G2012LandesBioscience
Mutual cross-talk between fibronectin integrins and the EGF receptor
Molecular basis and biological significance
Nikolas Balanis1 and Cathleen R. Carlin1,2,3,*
1DepartmentofPhysiologyandBiophysics;SchoolofMedicine;CaseWesternReserveUniversity;Cleveland,OHUSA;2DepartmentofMolecularBiologyand
Microbiology;SchoolofMedicine;CaseWesternReserveUniversity;Cleveland,OHUSA;3CaseWesternReserveUniversityComprehensiveCancerCenter;
SchoolofMedicine;CaseWesternReserveUniversity;Cleveland,OHUSA
Extension of the plasma membrane with previous observations linking
is one of the first steps in cell p190RhoGAP to RhoA-dependent cyto-
migration. Understanding how cells skeletal rearrangements involved in cell
“choose” between various types of mem- migration, and provide new data that
© 2012 Landes Bioscience.
brane protrusion enhances our know- the EGF receptor is compartmentalized
ledge of both normal and cancer cell to relatively immature zyxin-poor focal
physiology. The EGF receptor is a adhesions which are the likely site of
paradigm for understanding how trans- p190RhoGAP signaling.
membrane receptor tyrosine kinases
regulate intracellular signaling following
Do not distribute.
ligand stimulation. Evidence from the Allosteric Mechanisms
past decade indicates that EGF receptors for EGFR Activation
also form macromolecular complexes
with integrin receptors leading to EGF EGF receptors (EGFR) form molecular
receptor transactivation during cell adhe- complexes with multiple integrin extra-
sion. However, relatively little is known cellular matrix receptors leading to EGFR
about how these complexes form and transactivation and fine-tuning of adhe-
impact cell migration. Our recent work sion-induced cell signaling responses.1-3
characterized a molecular complex HowEGFRactivationisachievedremains
between EGF receptor and β3 integrin an active area of investigation. On the
Keywords: β3 integrin, EGF receptor, which recognizes RGD motifs in extra- one hand, adhesion-activated integrins
focal adhesion, p190RhoGAP, RhoA cellular matrix proteins. Complex forma- may sequester EGFRs leading to receptor
tion requires a dileucine motif (679-LL) oligomerization and activation independ-
Abbreviations: EGFR, EGF receptor; intheintracellularjuxtamembraneregion ent of soluble ligand. Alternatively or
FA,focaladhesion;FAK,focaladhesion of the EGF receptor that also controls perhaps in concert with increased receptor
kinase;FN,fibronectin;JM,juxtamembrane whether or not the receptor undergoes density, adhesion-induced Src kinase
Src kinase-dependent phosphorylation at activity may have a critical role in EGFR
Submitted: 12/01/11
Tyr-845. In contrast to wild-type recep- transactivation. Src kinase phosphorylates
Revised: 03/05/12; 03/21/12 tors, mutant EGF receptors defective for EGFRresidueTyr-845whichislocatedin
Accepted: 03/22/12 Tyr-845phosphorylationformcomplexes the activation loop of the EGFR catalytic
with β1 integrin that also binds RGD domain.4 The corresponding tyrosine resi-
http://dx.doi.org/10.4161/cl.20112
motifs. In addition, we have discovered dues in other receptor tyrosine kinases
*Correspondenceto:CathleenR.Carlin;
that EGF receptor antagonizes small are autophosphorylated following ligand
Email:[email protected]
GTPase RhoA by mediating membrane stimulation and phenylalanine substitu-
recruitment of its regulatory GAP tions significantly impair kinase signaling
Addendumto:BalanisN,YoshigiM,WendtMK,
SchiemannWP,CarlinCR.b3integrin-EGF p190RhoGAP. In this addendum we and downstream signaling. In contrast,
receptorcrosstalkactivatesp190RhoGAPin discuss a potential new role for Src- EGFR Tyr-845 phosphorylation is not
mousemammaryglandepithelialcells.MolBiol dependent EGF receptor transactivation required for ligand-induced EGFR activa-
Cell2011;22:4288–301;PMID:21937717;http:// inintegrin/EGFreceptorcomplexforma- tion but may instead represent a primary
dx.doi.org/10.1091/mbc.E10-08-0700
tion. We also discuss how our study fits mechanism for EGFR transactivation.4
46 CellularLogistics Volume2Issue1
ARTICLEADDENDUM
Our recently published results have iden- β3 integrin-EGFR complexes. β1 and β3 EGFR-p120RasGAP complex formation.5
tified a specific dileucine motif (679-LL) integrins both activate focal adhesion Second, EGFR (679-AA) which forms a
(see Box 1) located in the EGFR juxta- kinase (FAK) leading to activation of complex with β1 integrin does not recruit
membrane (JM) domain that is absolutely Src kinase.13 However, β3 integrins also p120RasGAP.5 We also provide new
required for Tyr-845 phosphorylation promote Src activation via direct interac- data that wild-type EGFR promotes
during cell adhesion.5 These results were tions between Src and β3 integrin cyto- p190RhoGAP tyrosine phosphorylation
obtained by adhering cells to the extra- plasmic tails.14 Our data therefore raise necessary for p120RasGAP-p190RhoGAP
cellular matrix protein fibronectin (FN) two interesting possibilities that are complex formation (Fig.1A). Similar to
containinganRGDsequence(Arg-Gly-Asp) not mutually exclusive. First, Tyr-845 cells reconstituted with wild-type EGFR,
recognizedbyseveralintegrinreceptors.Our phosphorylation may be preferentially p190RhoGAP is tyrosine phosphorylated
studies were focused on RGD-directed β1 mediatedbySrckinaseactivatedviadirect (Fig.1A) and also antagonizes RhoA acti-
integrin and β3 integrin receptors. interaction with β3 integrin cytoplasmic vity in newly adherent EGFR-null cells.5
EGFR 679-LL was originally identified tail.Second,β3integrin-EGFRcomplexes Althoughthemechanismforp190RhoGAP
as a lysosomal sorting signal following may be stabilized by interactions between activation in the EGFR-null cells is not
ligand-stimulated EGFR downregulation.6 SrcanditsEGFRsubstrateTyr-845.Thus known, previous studies indicate that
A 679-AA substitution does not affect alternative integrin-Src activation events p120RasGAP-p190RhoGAP membrane
ligand-induced internalization but pro- may determine the integrin constituents recruitment is mediated by FAK follow-
motes EGFR recycling and enhanced of the integrin-EGFR complex. ing FN engagement.20 Our data suggest
activation of a subset of EGFR tyrosine the mechanism of p190RhoGAP mem-
kinase substrates in recycling endosomes.7 Integrin-EGFR Complex Formation brane recruitment has a dramatic effect
© 2012 Landes Bioscience.
Subsequently, this motif was shown to and p190RhoGAP Activation on cell morphology.5 The EGFR-null
have a critical role in ligand-induced cells form prominent vertical stress fibers
EGFR activation. An important study by The small GTPase RhoA is a well-known (Fig.1B), compared with cells reconsti-
Zhang et al. showed that EGFR is acti- regulator of actin cytoskeletal rearrange- tuted with wild-type EGFR that form
vated by an allosteric mechanism involv- ments associated with formation of focal abundant filopodial extensions (Fig.1C).
ing formation of an asymmetric dimer in adhesions (FAs), actin stress fibers, and Remarkably, EGFR (679-AA) expression
Do not distribute.
which one kinase domain induces an filopodia and lamellipodia membrane abolishes adhesion-induced p190RhoGAP
active conformation in the other.8 This protrusions.15-17 Previous reports have tyrosinephosphorylation(Fig.1A).Further-
occurs through intra-molecular interac- shown that RhoA is antagonized by more, RhoA inhibition which usually
tions between the C-terminal lobe of a p190RhoGAP, the most abundant GAP accompanies cell adhesion, is compromised
“activator” kinase domain and the for RhoA in mammalian cells, during the in cells expressing EGFR (679-AA),5 and
N-terminal lobe of a “acceptor” kinase early stages of cell adhesion.16 To become this dominant-inhibitory phenotype is
domain leading to its catalytic activation.8 fully active p190RhoGAP must be tyro- associated with formation of broad lamel-
In this model 679-LL resides in the sine phosphorylated by Src kinase, form a lipodial membrane protrusions (Fig.1B).
asymmetric dimer interface adjacent to a complex with p120RasGAP, and undergo We cannot assess whether complex for-
JM segment that latches the “acceptor” recruitment to the cell periphery.16,18,19 mation between β1 integrin and EGFR
domaintotheactivatordomaintoachieve Differentmembranetargetingmechanisms (679-AA) represents a physiological signal-
full activation of EGFR.9-11 We speculate have an important role in determining ing unit or an experimental artifact due to
that integrin/EGFR complex formation the effect of local changes in GTP Rho the introduction of the dialanine substi-
triggers conformational changes in the activity. Our recent study showed that tution. However, these results raise the
activationloopthatmakeTyr-845accessi- EGFR mediates p190RhoGAP activation possibility that EGFR may inhibit certain
ble to Src kinase. 679-AA does not block by promoting its membrane recruitment.5 adhesion-induced responses. Overall our
integrin complex formation per se, but In this context, p120RasGAP serves as a results have uncovered an unexpected role
interferes with Tyr-845 exposure prevent- bridge, physically linking EGFR and for EGFR in p190RhoGAP activation
ing EGFR transactivation by Src kinase. p190RhoGAP. We found that adhesion- during formation of membrane protrusions
Ourdataareconsistentwithamodelin activated EGFRs form a complex with involved in cell migration.5 They also
which the 679-LL motif is necessary to p120RasGAP, EGFR-p120RasGAP com- underscore the critical role p190RhoGAP
form a stable β3 integrin-EGFR complex. plex formation is associated with a reduc- membrane recruitment has on allowing
However, EGFRs form complexes with tion in RhoA activity, and p190RhoGAP cells to switch between different types of
different integrin receptors in other cell is recruited to the cell periphery where cytoskeletal rearrangements.
models.12 How then is integrin-EGFR it co-localizes with EGFR.5 Two lines
complex formation regulated? Based on of evidence indicate the β3 integrin/ p190RhoGAP Activity
the resistance of EGFR (679-AA) to Src- EGFR axis is primarily responsible for and Focal Adhesions
dependent Tyr-845 phosphorylation, we p190RhoGAP activation. First, a D119A
hypothesize that Src kinase has a critical inhibitory mutation in β3 integrin Upon engagement of extracellular matrix,
role in assembling and/or stabilizing that blocks RGD binding inhibits integrins cluster and recruit various
www.landesbioscience.com CellularLogistics 47
one of the first proteins recruited to
newly formed FAs, when cells are adhered
to FN.5,17 Here we extend these studies
by examining additional FA proteins, the
actin binding protein a-actinin and the
anchor protein zyxin, which serve as
markers for mid and late stage FAs,
respectively.17 a-actinin is concentrated
in elongated FAs at stress fiber tips in
EGFR-null mouse fibroblasts (Fig.1B).
Similar to vinculin, a-actinin is enriched
at the base of filopodial actin filaments
in cells with wild-type EGFR (Fig.1C).5
Cells with EGFR (679-AA) display a
distinct a-actinin staining pattern charac-
terized by small puncta at the cell peri-
phery along with periodic staining in the
dense cortical actin region and the sparse
actin network in the lamellum. The late
stage FA marker zyxin is recruited to
© 2012 Landes Bioscience.
FAs at stress fiber tips in EGFR-null
mouse fibroblasts (Fig.2A). In contrast,
cells expressing either wild-type or
mutant EGFR were characterized by a
statistically significant reduction in zyxin
incorporation at peripheral adhesion com-
Do not distribute.
plexes compared with EGFR-null cells
(Fig.2B–D).
Altogether our data suggest EGFR is
compartmentalized to relatively immature
FAs during cell adhesion (Fig.3A). As
FAs mature they grow in size and incor-
porate additional constituent molecules.24
Immature FAs are smaller in size and
relatively short-lived. This may explain
why EGFRs form complexes with β3
integrin since a β is relatively enriched
v 3
in zyxin-negative FAs compared with
Figure1.(A)EGFRmodulatesFN-dependentphosphorylationofp190RhoGAP.FN-dependent other RGD directed integrin receptors23
adhesionassayswereperformedaspreviouslydescribed.5Briefly,cellswereadheredtoFNfor1h (Fig.3A). β3 integrin/EGFR compart-
andp190RhoGAPimmunecomplexeswereanalyzedbySDS-PAGEfollowedbyimmunoblotting
mentalization could serve two purposes.
withphosphotyrosineorp190RhoGAPantibodies.p190RhoGAPundergoestyrosinephosphoryla-
First, it may confine EGFR-dependent
tioninEGFR-nullfibroblasts(left),andcellsreconstitutedwithwild-typeEGFR(middle),but
notincellsexpressingEGFR(679-AA)(right).(B –D)EGFRmodulatesα-actinindistribution. p190RhoGAP activation to relatively
ConfocalprojectionsofEGFR-nullcells(B)andcellswithWT-EGFR(C)orEGFR(679-AA)(D)adhered immatureFAs.Second,compartmentaliza-
toFNfor20minco-stainedwithphalloidantovisualizeactin(red)anda-actininantibody(green). tion may contribute to the reduction in
Magnifiedimagesofindividualandmergedchannelsforboxedareasareshowntoright.Scale
stress fiber formation. Zyxin is recruited
bars,10mM.
to FAs under increased tension.25 Zyxin
also senses mechanical load and enhances
actin polymerization at FAs contributing
anchor/adaptor and signaling proteins to localized to FAs during cell adhesion.20 to stress fiber growth.25-27 Membrane
help form FAs.21 Adaptor proteins such FAs are formed by sequential recruitment p190RhoGAP recruitment to mature
as p130Cas, vinculin, a-actinin and zyxin of different anchor proteins that are FAs is probably mediated by FAK in
provide links to the actin cytoskeleton, involved in binding the actin cytoskeleton EGFR-null cells11 (Fig.3B). Thus EGFR
allowing for the formation of tension to the membrane.22,23 Our recent studies may reduce stress fiber formation by
necessary tochange cell morphology.21 The showed that EGFR expression is associ- driving a switch in how p190RhoGAP is
RhoA antagonist p190RhoGAP is also ated with altered distribution of vinculin, activated.
48 CellularLogistics Volume2Issue1
significant role in this selection process. It
has also been shown that the p130Cas
signaling adaptor is required for EGFR
complex formation with integrins recog-
nizing RGD motifs,12 and we suspect
additional adaptor proteins have yet to
be identified. Integrin/EGFR complex
formation and its impact on adhesion-
induced signaling have traditionally been
viewed as distinct processes. We propose
that these processes are intimately linked
and that regulation is bidirectional. The
ability of EGFR to switch integrin bind-
ing partners is probably important in
allowing cells to parse and adjust to
extracellular cues in a physiological con-
text. Data from this addendum suggest
that EGFR/integrin complexes are
resident in immature FAs which have a
higher rate of turnover compared with
© 2012 Landes Bioscience.
mature FAs.21 Because of their constant
turnoverimmatureFAscanrapidlysample
and adjust to the extracellular environ-
ment. Rapid turnover is also necessary
for cell migration. Thus immature FAs
represent an ideal platform to integrate
Do not distribute.
information from extracellular cues to
regulate formation of membrane protru-
sions. We also suspect interactions with
different RGD-containing extracellular
matrix proteins may influence formation
of distinct integrin/EGFR complexes.
As in vivo environments are seldom
homogeneous in matrix composition,
cells undoubtedly integrate signals from
many distinct EGFR/integrin complexes
simultaneously. How these signals are
interpreted and their hierarchy in rela-
tion to membrane protrusion outcomes
is an interesting future direction. We
believe these questions will further
Figure2.(A–C)EGFRiscompartmentalizedtozyxin-poorfocaladhesions.Confocalimagingwas establish a pivotal role for the EGFR
performedaspreviouslydescribed.5EGFR-nullcells(A)andcellswithwild-typeEGFR(B)orEGFR in allowing cells to switch between
(679-AA)(C)wereadheredtoFNfor20minandco-stainedwithphalloidan(red)andzyxin different mechanisms of membrane
antibody(green).Magnifiedimagesofindividualandmergedchannelsforboxedareasareshown
protrusion and hence regulate cell
toright.AsterisksindicatezyxinpositiveFAs.Scalebars,10mM.(D)Barsrepresenttheaverage
migration in response to a dynamic
numberofzyxin-positiveadhesioncomplexes20minpost-adhesiontoFN.Whitebar,EGFR-null
cells;lightgraybarkcellswithWT-EGFR;darkgraybar,cellswithEGFR(679-AA).Asterisksindicate microenvironment.
differencesbetweencellsthatwerestatisticallysignificant(p,0.001)asdeterminedbyStudent’s
t-test.Theseresultsshowasignificantreductioninzyxin-positiveFAsincellsexpressingeitherform Acknowledgments
ofEGFR.
Supported by T32 HL007653 (N.B.),
RO1 GM081498 (C.R.C.), and a pilot
Perspectives question relates to how EGFR chooses project grant from development funds
to interact with different RGD directed of the Case Comprehensive Cancer
Our work raises several interesting ques- integrin binding partners. Our data sug- Center Support Grant P30 CA043703
tions for future investigation. The first gest integrin/Src cross-talk may have a (C.R.C.).
www.landesbioscience.com CellularLogistics 49
Figure3.EGFRregulatesRhoA-mediatedcytoskeletalrearrangementsbyreconfiguringp190RhoGAPactivation.TobecomefullyactivetheRhoA
antagonistp190RhoGAPmustbetyrosinephosphorylatedbySrckinase,formacomplexwithp120RasGAP,andundergorecruitmenttothecell
periphery.OurdatasuggestthatEGFRhasanimportantroleindeterminingtheeffectoflocalchangesinGTP-Rhoactivitybyregulatingp190RhoGAP
membranerecruitment.(A)SimplifiedschematicdepictingEGFR-expressingcelladheredtofibronectin.b3integrinligationactivatesFAKandalso
©promote sco2mplex0formati1onwith2EGFR.b 3Lintegrian-EGFRncompldexeslocealizetsorelat iveBlyimmaitureo,zyxin-spoorFcAs.EGiFRerecruitnsp120RcasGAPe.
whichservesasabridgetop190RasGAPleadingtoformationoffilopodia.(B)EGFR-nullcelladheredtofibronectin.RGD-directedabintegrinsactivate
FAKwhichservesasascaffoldtorecruitp120RasGAPtomaturezyxin-positiveFAs.p120RasGAPfacilitatesabridgebetweenFAKandp190RasGAP
leadingtoformationofactinstressfibers.
Box1.Glossary.
679-LL:DileucinemotifinDEGFRjuoxtamem brnanedoomainretquir eddforSrckiinasse-metdiaterdTyir-84b5phospuhorylattioneandb3.integrincomplexformation;
679-AAsubstitutionsblocktheseactivities.
a-actinin:Actinfilamentcross-linkingandbundlingprotein;commonlyusedmarkerformid-stagefocaladhesions.
Fibronectin(FN):High-molecularweightglycoproteinoftheextracellularmatrixwithanRGDmotifthatbindstomembrane-spanningintegrinreceptors.
Focaladhesions(FA):Large,dynamicproteincomplexesatcellsurfaceconnectingactincytoskeletontoextracellularmatrix.
Focaladhesionkinase(FAK):Cytosolicproteintyrosinekinaserecruitedtoearly-stagecell-matrixadhesionswhichmediatesmanydownstream
responses.
p120RasGAP:AnegativeregulatorofRassignalingthatalsoformsacomplexwithp190RhoGAPcontributingtoGTPaseRhoAinhibitionduringcells
adhesion;maybinddirectlytoactivatedgrowthfactorreceptorsviaanSH2domain.
p190RhoGAP:ThemostprominentGAPforGTPaseRhoAinmammaliancells;probablylinkedtoactivatedgrowthfactorreceptorsthrough
p120RasGAp;antagonizesRhoAduringcelladhesion.
RGD(Arg–Gly–Asp):Conservedmotiffoundinavarietyofadhesiveproteinspresentinextracellularmatricesincludingfibronectin,vitronectin,and
osteopontin;b1andb3integrinsareRGD-directedadhesionreceptors.
RhoA:SmallGTPaseknowntoregulateactincytoskeletalrearrangementsassociatedwithformationoffocaladhesions,actinstressfibers,andfilopodia
andlamellipodiamembraneprotrusions.
Tyrosine-845:TyrosineresidueresidingintheEGFRactivationloopwhichisphosphorylatedbySrckinase;notrequiredforligand-mediatedEGFR
activation.
Srckinase:Non-receptortyrosinekinaseresponsibleforphosphorylatingTyrosine845ontheEGFR;presentinintegrin/EGFRcomplex.
Vinculin:Cytosolicproteininvolvedinattachingactincytoskeletontoplasmamembrane;commonlyusedmarkerforearly-stagefocaladhesions.
Zyxin:Cytosolicproteininvolvedinactinpolymerizationatfocaladhesions;commonlyusedmarkerformaturefocaladhesions.
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www.landesbioscience.com CellularLogistics 51