Integrin beta-2

Abstract

Integrins are heterodimeric transmembrane (TM) glycoproteins containing one each of α and β subunit, which are held together by non-covalent forces. Integrin β2 (CD18) is the β subunit for four heterodimers: αDβ2, αXβ2, αMβ2 and αLβ2. Integrin β2 family plays an essential role in leukocyte recruitment and activation during inflammation. Structurally, while most part of the αβ dimer is extracellular, both the subunits traverse the plasma membrane and terminate as short cytoplasmic domains. Each heterodimeric integrin exists on the cell surface mainly in an inactive (bent) form until they receive stimulating signals from other receptors (via inside-out signaling), and the end result of integrin activation is a shift in integrin conformation from a bent to an extended one. The binding of cytoplasmic proteins to α- and/or β-subunit carboxy-terminal tails is an essential part of the activation process, as these interactions stabilize the extended integrin conformation and provide connections to the cytoskeleton. The binding of extracellular ligand to the extended form of integrin (via outside-in signaling) triggers a large variety of signal transduction events that modulate cell behaviors such as adhesion, proliferation, survival or apoptosis, shape, polarity, motility, and differentiation, mostly through effects on the cytoskeleton. The receptors αMβ2 (Complement Receptor type 3, CR3) and αXβ2 (Complement Receptor type 4, CR4) are regarded to be the most important mediators for complement-driven phagocytosis.

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UCSD MOLECULE PAGES
Integrin beta-2
Ashok Reddy Dinasarapu1, Anjana Chandrasekhar1, George Hajishengallis2, Shankar Subramaniam3
Review Article Open Access
Integrins are heterodimeric transmembrane (TM) glycoproteins containing one each of α and β subunit, which are held
together by non-covalent forces. Integrin β2 (CD18) is the β subunit for four heterodimers: αDβ2, αXβ2, αMβ2 and αLβ2.
Integrin β2 family plays an essential role in leukocyte recruitment and activation during inflammation. Structurally, while
most part of the αβ dimer is extracellular, both the subunits traverse the plasma membrane and terminate as short cytoplasmic
domains. Each heterodimeric integrin exists on the cell surface mainly in an inactive (bent) form until they receive stimulating
signals from other receptors (via inside-out signaling), and the end result of integrin activation is a shift in integrin
conformation from a bent to an extended one. The binding of cytoplasmic proteins to α- and/or β-subunit carboxy-terminal
tails is an essential part of the activation process, as these interactions stabilize the extended integrin conformation and provide
connections to the cytoskeleton. The binding of extracellular ligand to the extended form of integrin (via outside-in signaling)
triggers a large variety of signal transduction events that modulate cell behaviors such as adhesion, proliferation, survival or
apoptosis, shape, polarity, motility, and differentiation, mostly through effects on the cytoskeleton. The receptors αMβ2
(Complement Receptor type 3, CR3) and αXβ2 (Complement Receptor type 4, CR4) are regarded to be the most important
mediators for complement-driven phagocytosis.
KEYWORDS
CD18; Cell surface adhesion glycoprotein LFA-
1/CR3/P150,959 beta subunit precursor); Cell surface adhesion
glycoproteins LFA-1/CR3/p150,95 subunit beta; Complement
receptor C3 beta-subunit; Complement receptor C3 subunit
beta; Integrin beta chain, beta 2; Integrin beta-2; Integrin, beta
2 (complement component 3 receptor 3 and 4 subunit); ITGB2;
LAD; LCAMB; Leukocyte cell adhesion molecule CD18;
Leukocyte-associated antigens CD18/11A, CD18/11B,
CD18/11C; LFA-1; MAC-1; MF17; MFI7
IDENTIFIERS
Molecule Page ID:A004263, Species:Human, NCBI Gene ID:
3689, Protein Accession:NP_001120963.1, Gene
Symbol:ITGB2
PROTEIN FUNCTION
Inflammation which occurs due to infection or tissue injury,
controls a cascade of cellular and microvascular reactions that
allow the removal of pathogens or cell debris, and finally give
rise to wound healing, repair and homeostasis. The process of
the inflammation includes recruitment (migration) of free-
flowing immune cells such as polymorphonuclear neutrophils
(PMN) and monocytes/macrophages to the site of infection
(Simon and Green 2005; Nourshargh et al. 2005). The
essential steps during leukocyte recruitment includes tethering
and rolling, activation, firm adhesion, intraluminal crawling,
and extravasation. Firm adhesion and crawling are largely
mediated by β2-integrins (Kolaczkowska and Kubes 2013,
Hajishengallis and Chavakis 2013). Signaling via adhesion
molecules of the β2 integrin family plays an essential role for
immune cell recruitment and activation during inflammation.
An important function of these recruited leukocytes is the
phagocytosis of complement opsonized particles mediated by
integrin αMβ2 (Anderson and Springer 1987). Therefore,
integrin β2-mediated leukocyte migration contributes crucially
to the performance of the immune defense system.
Integrin structure: Integrins are noncovalently associated αβ
heterodimeric cell surface glycoproteins. The known 18 α and
8 β subunits in humans generate 24 different heterodimeric
receptors, each of which exhibits distinct ligand-binding
specificities and tissue distribution (Takada et al. 2007; Hynes
2002). Both the α and β subunits are type I membrane proteins
(single-pass transmembrane (TM) proteins, which have their N-
terminus exposed to the extracellular or luminal space), with a
large extracellular ligand-binding region (a.k.a ectodomain) and
generally a short cytoplasmic tail that binds multiple
cytoskeletal and adaptor/signaling proteins that regulate the
affinity of integrin for extracellular ligands (Hynes 2002;
Suzuki and Naitoh 1990; Anthis and Campbell 2011). The
integrin heterodimers adopt a shape that resembles a large
“head” on two “legs,” with the head containing the sites for
ligand binding and subunit association (Campbell and
Humphries 2011). The extracellular region of the α subunit is
composed of a β- propeller fold with seven blades (W1-W7), a
Thigh domain, and two Calf domains (Calf-1 and Calf-2)
(Xiong et al. 2001; Zhu et al. 2009; Xie et al. 2010). Further, an
I-(inserted or αA) domain (in β- propeller) is present in nine of
the α subunits (Lee et al. 1995). The extracellular region of the
β subunit is composed of a plexin-semaphorin-integrin (PSI)
domain, an I-like (or βA) domain, a hybrid domain, four
integrin-epidermal growth factor (I-EGF1 to I-EGF4) folds and
a β tail domain (βTD) (Xiong et al. 2001; Zhu et al. 2009; Xie
et al. 2010; Tan et al. 2001; Shi et al. 2007; Shi et al. 2005; Zhu
et al. 2008). The I-like domain is inserted into hybrid domain,
which in turn is inserted into PSI domain. The two α-helical TM
domains of a resting integrin adopt a ridge-in-groove packing
(Zhu et al. 2009; Lau et al. 2009) and the association of the TM
domains is specific (Vararattanavech et al. 2008). The
cytoplasmic tails of the β subunits (other than β4 and β8)
contain one or two highly conserved NxxY/F motifs (x
represents other amino acids) that can recognize a wide variety
of signaling and cytoskeletal proteins (e.g. adaptor molecules
such as ILK, DAB1, Dok-1 and FHL2) that connects integrins
to the actin cytoskeleton or activate a range of signaling
pathways. In contrast, apart from having a highly conserved
juxtamembrane GFFKR motif, α cytoplasmic tails are divergent
in their lengths and sequences.
1Department of Bioengineering, University of California, San Diego, CA 92093, US. 2School of Dental Medicine, University of Pennsylvania, PA 19104, US. 3Department of Bioengineering,
University of California at San Diego, CA 92093, US.
Correspondence should be addressed to Ashok Reddy Dinasarapu: adinasarapu@ucsd.edu
Published online: 31 Oct 2013 | doi:10.6072/H0.MP.A004263.01
doi:10.6072/H0.MP.A004263.01
Volume 2, Issue 2, 2013
Copyright UC Press, All rights reserved.
www.signaling-gateway.org

Integrin β2 family genes and selectivity: The human CD18
gene, a.k.a ITGB2, is located on chromosome 21q22.3 and
encodes a 95-kDa glycoprotein, Integrin β2 (Kishimoto et al.
1987). The human CD11 genes such as ITGAL, ITGAM,
ITGAX and ITGAD are located on chromosome 16p11.2 and
encode glycoproteins αL (CD11a, 180kDa), αM (CD11b,
160kDa), αX (CD11c, 150kDa) and αD (CD11d, 145 kDa),
respectively (Tan 2012; Fu et al. 2012; Luo et al. 2007).
Integrin β2, exclusively expressed on leukocytes, forms
heterodimers with the above four α subunits and these
heterodimers are signal transducer receptors involved in
phagocytosis, degranulation and cell adhesions. Even though
β2 integrin is common to all these heterodimers, differences in
divergent α tails confer structural variations between these
integrins. For example, αLβ2 and αMβ2 integrins show distinct
chemokine-induced activation kinetics (Weber et al. 1999),
sites for the docking of specific cytosolic molecules such as
selective recruitment of the Src kinase Hck to αMβ2 but not
αLβ2 (Tang et al. 2006), and specific association of CD45
cytoplasmic domain with αL (Geng et al. 2005). See
‘Interactions with Ligands and Other Proteins’ section for
further details.
Leukocyte migration/adhesion: The movement of leukocytes
from the bloodstream to the tissue occurs in several distinct
steps as explained above. The β2 integrin family of adhesion
molecules plays a central role in firm adhesion and subsequent
crawling on the endothelium, during which leukocytes seek an
appropriate site for diapedesis through endothelial junctions
(Grönholm et al. 2011; Gahmberg et al. 1999). See
‘Interactions with Ligands and Other Proteins’ section for
further details.
Phagocytosis: Phagocytosis is a physiological process by
which specialized cells (e.g. macrophages) recognize, bind and
internalize materials such as cell debris, microbes,
necrotic/apoptotic cells through the use of phagocytic receptors
such as Fcγ receptors (utilizes membrane pseudopods),
scavenger receptors (mediates binding to modified lipoprotein
particles) or integrins (utilizes membrane ruffle mechanism).
Integrin activation through bidirectional (inside-out and
outside-in) signaling leads to the interaction between particle
and integrin which results in an actin-driven uptake of the
particle. Activated integrins link actin dynamics to
extracellular components that involves cytoskeletal remodeling
and cell-shape changes during phagocytosis. However, integrin
signaling is also exploited by a variety of pathogens for entry
into host cells (Dupuy and Caron 2008). See ‘Interactions with
Ligands and Other Proteins’ section for further details.
REGULATION OF ACTIVITY
Integrins lack enzymatic (intrinsic) activity and the interactions
between the membrane proximal regions of α and β are crucial
for maintaining integrins in resting state (Chua et al. 2011).
Integrins use classical bidirectional (a.k.a inside-out and
outside-in) signaling and non-classical signaling processes
(integrin clustering and membrane ruffling) to integrate the
intracellular and extracellular environments (Lim and Hotchin
2012). Inside-out signaling refers to intracellular signaling
events that result in a higher-affinity state of the ectodomain of
integrin for its cognate ligands. Regulatory events that mediate
inside-out signaling converge on the cytoplasmic tails of the α
and β chains, which transduce signals to their ectodomains
(Dustin et al. 2004).
Intracellular signaling pathways, which regulate the
interactions of integrins with their ligands, affect a wide variety
of biological functions. Integrin activation is usually initiated by
integrin β subunit cytoplasmic tail (Calderwood et al. 1999)
through the recruitment of cytosolic proteins and many of these
interactions are modulated by tail phosphorylation (Gahmberg
et al. 2009; Fagerholm et al. 2004; Liu et al. 2000). Signaling
molecules implicated in inside-out signaling through αLβ2
include talin, Vav1, PKD1, several adaptor proteins (SLP-76,
ADAP, and SKAP-55), the Ras family GTPase Rap1, and two
of its effectors, RAPL and RIAM (Ménasché et al. 2007). Apart
from talin, kindlin-3 was shown to bind to, and activate Integrin
β2 and that a direct interaction of kindlin with the β subunit
cytoplasmic tail is required, but not sufficient, for integrin
activation (Moser et al. 2009). Integrin-linked kinase (ILK)
interacts with the cytoplasmic domains of integrin β2 (also β1
and β3) (Hannigan et al. 1997; Hannigan et al. 1996;
Delcommenne et al. 1998) which acts as a proximal receptor
kinase that regulates integrin-mediated signal transduction.
Spleen tyrosine kinase (Syk) is constitutively associated with
the cytoplasmic tail of β2 integrin (Willeke et al. 2003;
Woodside et al. 2002). Syk is known to be phosphorylated and
activated upon β2 integrin mediated adhesion (Mócsai et al.
2002; Willeke et al. 2003). Syk and Zap-70 (Zeta-chain-
associated protein kinase) are non-receptor cytoplasmic tyrosine
kinases with two Src homology (SH)2- domains, a kinase
domain and two interdomians (A and B). Syk and Zap-70
transmit signals from the immune receptors (B-Cell receptor
and T-Cell receptor), CD74, Fc Receptor and integrins (Mócsai
et al. 2002; Turner et al. 2000). The inside-out activation leads
to an increase in the binding affinity of integrin ectodomains for
their extracellular ligands (known as ‘outside-in’ activation)
(Calderwood et al. 1999; Tadokoro et al. 2003; Li et al. 2007;
Wegener et al. 2007; Lim et al. 2007; García-Alvarez et al.
2003; Calderwood 2004). Outside-in signaling is analogous to
signaling by conventional receptors and is defined as
stimulation of intracellular signaling pathways as a consequence
of ligation of αLβ2 with any of its extracellular ligands, such as
intracellular adhesion molecule 1 (ICAM-1). Guanine
nucleotide exchange factors Cytohesin-1 and Cytohesin-3,
activated by PI(3,4,5)P3, bind β2 integrin which leads to an
increase cell adhesion through an affinity-independent
processes, such as integrin clustering, rather than integrin
activation (Calderwood 2004). Cytohesin-1 interacts with the
cytoplasmic domains of the integrin β-chain common to all β2
integrins such as αLβ2 and αMβ2 and regulates cell adhesion
(Geiger et al. 2000; Hyduk and Cybulsky 2011; El Azreq et al.
2011).
αMβ2 also mediates events (classified as non-classical) such as
integrin clustering and membrane ruffling in a ligand
independent fashion in macrophages following treatment with
phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide
(LPS) (Patel and Harrison 2008; Williams and Ridley 2000).
The bacterial endotoxin LPS is a potent stimulator of
monocyte/macrophage activation and induces adhesion of
monocytes while PMA is used in monocyte differentiation. The
integrin clustering (in phagocytic function) occurs through the
cytoplasmic tails which is different from the extracellular
clustering (promotes differentiation to macrophage) of
monocyte integrins. The association of Rack1 to integrin β2
(coimmunoprecipitated with αLβ2) in vivo (Liliental and Chang
1998) requires a treatment with PMA which promotes cell
spreading and adhesion. These findings suggest that Rack1 may
link protein kinase C directly to integrin β2 and participate in
the regulation of integrin functions (Liliental and Chang 1998).
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Bacteria derived fMLP (N-formyl-Met-Leu-Phe, also known
as fMLF) induces chemotactic migration and it activates αMβ2
or αLβ2 in human neutrophils through vasodilator stimulated
protein (VASP) (Deevi et al. 2010) and cytohesin-1 (El Azreq
et al. 2011). Both VASP and cytohesin-1 function as ‘negative
regulators’ of inside-out function of αMβ2 (El Azreq et al.
2011). fMLP, activates Rap1 and inside-out signaling of β2
integrins (Deevi et al. 2010), triggers phosphorylation of
VASP on S239 and, thereby, controls membrane recruitment
of C3G (a guanine nucleotide exchange factor for Rap1),
which is required for activation of Rap1 and antibacterial (β2
integrin-dependent) functions of neutrophils.
INTERACTIONS
Integrins are heterodimeric (αβ) type I membrane receptors
which have their N-terminus exposed to the extracellular space
with a large extracellular ligand-binding region and a short
cytoplasmic tail that binds multiple cytoskeletal adaptor or
signaling proteins that regulate the affinity of integrin for
extracellular ligands. The adhesion of integrins to the
extracellular matrix is regulated by binding of the cytoskeletal
protein talin to the cytoplasmic tail of the β-integrin subunit.
Activation is initiated by tail separation and propagation of
conformational changes to the outside of the cell. Rap1, a
small GTPase, controls activation of integrin (αMβ2) in a talin-
dependent manner (Lim et al. 2010). Ligand interaction with
activated β2 integrins takes place via an inserted I-domain in
the α subunit (Shimaoka et al. 2003; Shimaoka et al. 2005).
Integrin αL I domains interact with β2 in the following orders
of affinity: ICAM-1 > ICAM-2 > ICAM-3 (Guermonprez et al.
2001). Leukocyte integrins αLβ2, αMβ2 and αXβ2 act as
collagen receptors and the α domains favor different collagen
subtypes and also differ in their requirements for activation
(Lahti et al. 2013).
αLβ2 (CD11a/CD18; Leucocyte Function-associated Antigen-
1, LFA-1): αLβ2, a leukocyte-restricted integrin, is essential
for the adhesion, migration, proliferation of leukocytes,
immune synapse formation, and NK cell cytotoxicity (Kinashi
2007; Smith et al. 2007; Bryceson et al. 2006; Bhunia et al.
2009). Ectopic expression of talin head domain induces αLβ2
activation possibly via association of talin head domain with
the membrane proximal NPXF motif in the β2 tail (Li et al.
2007; Kim et al. 2003). Another actin-binding protein -actinin
binds to the membrane proximal sequence of the β2 tail of
αLβ2 (Pavalko and LaRoche 1993; Stanley et al. 2008).
Interestingly, the binding of filamin to triplet Thr motif of the
β2 tail has an inhibitory effect on αLβ2-mediated T cell
adhesion (Takala et al. 2008) (Bhunia et al. 2009). RAPL
(regulator of adhesion and cell polarization enriched in
lymphoid tissues) associates with Rap1-GTP, and the
activating effect of this complex on αLβ2 requires the
membrane proximal Lys1097 and Lys1099 in the αL tail
(Tohyama et al. 2003). Collectively, a multifaceted (positive
and negative) regulatory network of molecules at the
cytoplasmic face of the αLβ2 allows fine-tuning of αLβ2
activity in cells under different contexts such as physiological
conditions, and in different regions of a polarized and
migrating cell (Chua et al. 2013). Studies in mice have led to
identification of developmental endothelial locus-1 (Del-1) as
an endogenous antagonist of LFA-1 (Choi et al. 2008) and it
inhibits transmigration to inflamed tissues (Eskan et al. 2012).
Integrin αLβ2 interacts with ICAM1-4. ICAM-1 is an
inducible molecule that is up-regulated by inflammatory
cytokines on endothelium, leukocytes, and multiple other cell
types, whereas ICAM-3 is constitutively expressed on
leukocytes and absent from endothelium and most other cell
types under normal conditions (Springer 1990; Fawcett et al.
1992). ICAM-1/αLβ2 interaction is essential for T-cell
activation as well as for migration of T-cells to target tissues
(Anderson and Siahaan 2003). CD47, also called Integrin
Associated Protein (IAP), has been demonstrated to associate
with β2 integrins. The interaction between Jurkat T-cell β2
integrins and CD47 were detected by fluorescence lifetime
imaging microscopy (Azcutia et al. 2013) and that CD47 is
necessary for induction of αLβ2 high affinity conformations that
bind to their ligand ICAM-1. ICAM-1, as a member of super-
IgG family, consists of five IgG-like domains (D1–D5) and
binds to αMβ2 via D3 domain (Diamond et al. 1991) and αLβ2
via D1 domain (Staunton et al. 1991), respectively. Cytohesin-1
interacts with the intracellular portion of the integrin β2 chain
(Kolanus et al. 1996). Colocalization of CD82 antigen or
Cytohesin-1 with αLβ2 at an adhesion foci results in enhanced
interaction between αLβ2 and ICAM-1 during T cell-T cell and
T cell-APC interactions (Shibagaki et al. 1999; Kolanus et al.
1996). Except αLβ2, all other β2 Integrins binds to Fibrin.
αMβ2 (CD11b/CD18; Complement Receptor type 3, CR3;
Macrophage-1 antigen, Mac-1; the iC3b receptor): αMβ2, a
leukocyte restricted integrin, mediates leukocyte migration,
adhesion, phagocytosis, degranulation and the maintenance of
immune tolerance. The receptor αMβ2 is regarded to be the
most important mediator for complement-driven phagocytosis.
Signaling via αMβ2 predominantly occur, in
polymorphonuclear neutrophils (PMN), upon ligand binding
and may have a unique role in neutrophil migration (Walzog et
al. 1996; Yan et al. 1997; Ross and Lambris 1982). Integrin
αMβ2 binds ligands such as intercellular adhesion molecule -1
(ICAM-1) on inflamed endothelial cells, the complement C3
(fragments such as iC3b), fibrinogen and fibrin, collagens and
coagulation factor X (Plow et al. 2000; Walzog et al. 1995).
Being expressed on phagocytes, it interacts with iC3b opsonized
pathogen (Bajic et al. 2013). Complement C3 deposition on the
bacterial surface and αMβ2 on the macrophage surface play
important roles in the uptake of the highly virulent Francisella
tularensis subsp. Tularensis, an infectious facultative
intracellular pathogen (Schulert and Allen 2006; Clemens et al.
2005; Clay et al. 2008). Complement receptors, particularly
αMβ2, have long been postulated to allow for safe passage for
intracellular pathogens (Wright and Silverstein 1983). There is
an increasing evidence for signaling crosstalk between
complement receptors and TLRs (Hajishengallis and Lambris
2010; Hajishengallis and Lambris 2011; Ivashkiv 2009). For
example, TLR2 is able to trans-activate αMβ2 through inside-
out signaling including the activation of Rac1, PI3K and
cytohesin-1 (Harokopakis et al. 2005; Sendide et al. 2005).
Integrin β2 signaling can also negatively regulate TLR
responses (Ivashkiv 2009; Wang et al. 2010). Specifically,
αMβ2 can inhibit TLR4 signaling by promoting the degradation
of MyD88 and TRIF (Han et al. 2010).
Integrin αMβ2's function is dependent on the activation of
outside-in and inside-out two way signals (Abram and Lowell
2009). Signaling via αMβ2 plays an important role in regulating
production of interleukin-12 (IL-12), a key mediator of cell-
mediated immunity (Marth and Kelsall 1997). In addition,
engagement of αMβ2 has been shown to down-regulate IL-12
production (Marth and Kelsall 1997) and avoid initiation of the
oxidative burst in macrophages following phagocytosis of
apoptotic cells (Kim et al. 2005). Known key players during
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Volume 2,Issue 2, 2013 35

inside-out activation of αMβ2 include Rap1, talin1 and
CamKII. CamKII phosphorylation of S756, allows Rap1 and
talin to be recruited to β2 and consequently activate αMβ2
(Lim et al. 2011). Ceramide, a constituent of atherogenic
lipoproteins, binds with CD14 (membrane anchored) and
induces clustering of CD14 with co-receptors in lipid rafts
(Ceramide recruits αMβ2 and CD36 to the proximity of
CD14). CD14 lacks a transmembrane signaling domain and
signals through TLR4 or TLR2 and plays a major role in the
inflammatory response of monocytes to LPS (Pfieffer et al.
2001).
Integrin αMβ2 is a known ligand of RAGE (Advanced
glycosylation end product-specific receptor) protein. RAGE
and αMβ2 have been shown by Ma et al. 2012 to interact with
C1q, both individually (αMβ2/RAGE and RAGE/C1q
complexes) and together as a complex (αMβ2/RAGE/C1q
complex) (Ma et al. 2012). The outcome of C1q interaction
with these proteins, is enhanced phagocytosis. The tri-complex
of αMβ2/RAGE/C1q shows more efficient phagocytosis than
C1q/RAGE or RAGE/αMβ2. RIAM (Rap1-interacting adaptor
molecule), in contrast to the previous study (Lim et al. 2010),
regulates the recruitment of talin (via Rap1) to αMβ2 in
complement-mediated phagocytosis in human myeloid cell
lines (HL-60 and THP-1) and macrophages derived from
primary monocytes (Lee et al. 2009; Medraño-Fernandez et al.
2013).
Integrin αMβ2 interacts with fimbriae of Porphyromonas
gingivalis (P. gingivalis) (Hajishengallis et al. 2007). P.
gingivalis (Harokopakis et al. 2005) and Mycobacterium bovis
BCG (Sendide et al. 2005) can activate αMβ2 through inside-
out signaling via TLR2 to facilitate bacterial uptake. CyaA
(Bordetella pertussis) uses the αMβ2 as a cell receptor and
CyaA intoxication leads to increased intracellular cAMP level
and cell death (Guermonprez et al. 2001). RrgA on
pneumococcal pilus 1 promotes nonopsonic αMβ2-dependent
uptake of S. pneumoniae by murine and human macrophages.
RrgA-αMβ2-mediated phagocytosis promotes systemic
pneumococcal spread from local sites (Orrskog et al. 2012).
Complement iC3b covalently bound to the gonococcus serves
as a primary ligand for αMβ2 adherence. However, gonococcal
porin and pili also bound to the I-domain of αMβ2 in a non-
opsonic manner. αMβ2-mediated endocytosis serves as a
primary mechanism by which N. gonorrhoeae elicits
membrane ruffling and cellular invasion of primary, human,
cervical epithelial cells and this data suggest that gonococcal
adherence to αMβ2 occurs in a co-operative manner, which
requires gonococcal iC3b-opsonization, porin and pilus
(Edwards et al. 2002; Jones et al. 2008). CD14 cooperates with
αMβ2 to mediate phagocytosis of Borrelia burgdorferi.
Complement enhances phagocytosis of B. burgdorferi in a C3-
dependent manner (Hawley et al. 2013). αM interacts with
leukocidin A/B (LukAB), which is produced by S. aureus upon
encountering neutrophils and is both necessary and sufficient
for S. aureus to kill human neutrophils, macrophages and
dendritic cells (DuMont et al. 2011, DuMont et al. 2013a). The
α subunit of the αMβ2 integrin acts as a cellular receptor for
LukAB (DuMont et al. 2013b).
αXβ2 (CD11c/CD18; p150,95; Complement Receptor type 4,
CR4): Integrin αXβ2 is a receptor for iC3b, C3dg, and C3d
fragments of complement C3 (Myones et al. 1988, Vik and
Fearon 1985; Chen et al. 2012; Micklem and Sim 1985) and
was shown to bind with apparently equal affinity (Vik and
Fearon 1985). Integrin αXβ2 also shares some functional
properties with αMβ2 as an adhesion surface molecule. Both
αMβ2 (Wright and Jong 1986) and αXβ2 bind bacterial LPS
and β-glucans and promote phagocytosis of unopsonized
bacteria and yeast. A large number of intracellular proteins have
been found to interact with the cytosolic tails (CTs) of this
integrin linking αXβ2 to the cytoskeleton (Chua et al. 2012).
αDβ2 (CD11d/CD18): Integrin αDβ2 is a multiligand
macrophage receptor with recognition specificity identical to
that of the major myeloid cell-specific integrin αMβ2. Integrin
αDβ2 is capable of supporting cell adhesion to various extra
cellular matrix (ECM) proteins, including fibronectin,
vitronectin, fibrinogen, CCN1 (Cyr61) and others. αDβ2,
selectively binds ICAM-3 and VCAM-1 and does not appear to
bind ICAM-1 (Van der Vieren et al. 1995; Van der Vieren et al.
1999; Grayson et al. 1998). The αD I-domain is responsible for
the binding function and that the mechanism whereby αD I-
domain recognizes its ligands is similar to that utilized by
αMβ2.
CMAP, a complement database, documents the biochemical
methods used to identify these interactions (Yang et al. 2013).
PHENOTYPES
Leukocyte emigration, from the bloodstream to tissue to sites of
inflammation, is a dynamic process and involve multiple steps
in an adhesion cascade. Various adhesion molecules are
expressed on both resting and stimulated endothelial cells and
leukocytes (Nagendran et al. 2012; Muller 2003). Leukocyte
adhesion and tethering defects involve β2 integrins and selectin
ligands (Bunting et al. 2002). Selectins are found on both
leukocytes and endothelial cells and primarily mediate cellular
margination and rolling. Defects in a number of these adhesion
molecules result in recognized clinical syndromes called
Leukocyte Adhesion Deficiency (LAD) syndrome in which
leukocytes (particularly neutrophils) cannot leave the
vasculature to migrate normally into tissues under conditions of
inflammation or infection. Affected individuals display blood
neutrophilia, suffer from recurrent infections, and invariably
develop agressive periodontitis leading to premature loss of
primary and permanent teeth (Bowen et al. 1982; Anderson and
Springer 1987; Arnaout 1990; Shaw et al. 2001; Wright et al.
1995; Etzioni 1999).
LAD I, in which the β2-integrin family is deficient or defective.
LAD II, in which the fucosylated carbohydrate ligands for
selectins are absent.
LAD III, in which the activation of β integrins (β1, β2, and β3)
are defective (Karaköse et al. 2010; Plow et al. 2009; Jurk et al.
2010). LAD III is mainly due to mutations in fermitin family
member 3 (FERMT3, aka KIND3). All LAD III patients have
premature stop codons or nonsense mutations in both alleles of
their FERMT3 gene (Malinin et al. 2009; Manevich-Mendelson
et al. 2009; Kuijpers et al. 2009; Svensson et al. 2009; Kuijpers
et al. 1997). Kindlin-3 is a cytoplasmic protein that acts
cooperatively with talin-1 in activating β1, β2, and β3 integrins.
LAD III is characterized by bleeding disorders and defective
recruitment of leukocytes into sites of infection.
MAJOR SITES OF EXPRESSION
αLβ2 (CD11a/CD18, LFA-1): Integrin αLβ2 is the only integrin
expressed on all leukocyte lineages.
αMβ2 (CD11b/CD18, CR3; Mac-1): Expressed on
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polymorphonuclear leukocytes (mainly, neutrophils),
mononuclear phagocytes (dendritic cells, monocytes and
macrophages), lymphocytes (mainly, natural killer (NK) and
γδ T-cells) and microglia.
αXβ2 (CD11c/CD18, CR4): Expressed on mononuclear
phagocytes (dendritic cells, monocytes and macrophages),
polymorphonuclear leukocytes (mainly, neutrophils), activated
B lymphocytes and natural killer (NK) cells.
αDβ2 (CD11d/CD18): Expressed on macrophages and
eosinophils.
SPLICE VARIANTS
Integrin β2 is a 95-kDa glycoprotein, encoded by the ITGB2
gene and is located on chromosome 21q22.3 (Kishimoto et al.
1987). Human ITGB2 spans approximately 40 kb of DNA and
contains 16 exons (Weitzman et al. 1991). Two transcript
variants encoding the same protein have been identified.
REGULATION OF CONCENTRATION
The expression of the leukocyte integrins is cell-specific and is
coordinately regulated during leukocyte differentiation through
transcriptional and post-transcriptional mechanisms (Miller et
al. 1986; Noti et al. 2001; Noti and Reinemann 1995; Back et
al. 1992). The promoters for the CD11a-d (Pahl et al. 1992;
Nueda et al. 1993; López-Rodríguez et al. 1995; Cornwell et
al. 1993; Noti et al. 1992; López-Cabrera et al. 1993; Agura et
al. 1992; Hickstein et al. 1992) and CD18 (Rosmarin et al.
1992; Agura et al. 1992) genes lack classical TATA boxes but
instead appear to be controlled by initiator elements positioned
within 100 bp of their ATG translational start codons. Cis
elements are found within 500 bp upstream of the ATG site,
some of which control cell-specific expression.
ANTIBODIES
Monoclonal antibodies (mAbs) directed against the CD18 (β2):
blocking IB4 (Bednar et al. 1996) and an activating KIM-127.
KIM127 is a widely used mAb that recognizes a β2 subunit
epitope (on epidermal growth factor (EGF)-like domain 2) that
is cryptic on bent αLβ2, but exposed when the integrin extends
(Beglova et al. 2002; Kamata et al. 2002; Chen et al. 2010).
Efalizumab is a monoclonal antibody, which is specific for
αLβ2 to treat psoriasis. Anti-integrin β2 mAb MEM-48 is
available from Sigma.
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Table 1: Functional States
STATE DESCRIPTION LOCATION REFERENCES
β2 (CD18) plasma membrane
β2/DAB1 integrin complex Calderwood DA et al. 2003
β2/FHL2 integrin complex Wixler V et al. 2000
β2/DOK1 integrin complex Calderwood DA et al. 2003
β2/PKC integrin complex Fagerholm S et al. 2002
β2/ILK integrin complex Hannigan GE et al. 1997; Delcommenne M et al. 1998
β2/(Syk|Zap-70) integrin complex Willeke T et al. 2003; Woodside DG et al. 2002; Miura Y et al. 2000
β2/Hsp40 (F. tularensis) integrin complex Dyer MD et al.
αDβ2 (CD11d/CD18) alphaD-beta2 integrin complex Van der Vieren M et al. 1995
αDβ2/VCAM-1 alphaD-beta2 integrin complex Grayson MH et al. 1998; Van der Vieren M et al. 1999
αDβ2/ICAM-3 alphaD-beta2 integrin complex Van der Vieren M et al. 1995
αDβ2/Fibrinogen alphaD-beta2 integrin complex Yakubenko VP et al. 2006
αMβ2 (CR3; CD18/11b) alphaM-beta2 integrin complex Arnaout MA et al. 1988; Sándor N et al. 2013
αMβ2/CD14 alphaM-beta2 integrin complex Pfeiffer A et al. 2001; Ross GD et al. ; Zarewych DM et al. 1996
αMβ2/CD23 alphaM-beta2 integrin complex Ross GD et al. ; Lecoanet-Henchoz S et al. 1995
αMβ2/CD59 alphaM-beta2 integrin complex Ross GD et al.
αMβ2/Collagen alphaM-beta2 integrin complex Ross GD et al.
αMβ2/Fibrinogen alphaM-beta2 integrin complex Diamond MS et al. 1993; Ross GD et al.
αMβ2/ELANE alphaM-beta2 integrin complex Cai TQ and Wright SD 1996
αMβ2/Heparan sulfate alphaM-beta2 integrin complex Ross GD et al.
αMβ2/fH alphaM-beta2 integrin complex DiScipio RG et al. 1998; Ross GD et al.
αMβ2/FX alphaM-beta2 integrin complex Altieri DC and Edgington TS 1988; Ross GD et al.
αMβ2/β-glucan alphaM-beta2 integrin complex Ross GD et al.
αMβ2/LN-8 alphaM-beta2 integrin complex Wondimu Z et al. 2004
αMβ2/GPIbα alphaM-beta2 integrin complex Josefsson EC et al. 2005
αMβ2/uPAR-GPI alphaM-beta2 integrin complex Pliyev BK et al. 2010; Ross GD et al. ; Xue W et al. 1994
αMβ2/uPAR-GPI/uPA alphaM-beta2 integrin complex
αMβ2/FcγRIIa (CR3/CD32) alphaM-beta2 integrin complex Annenkov A et al. 1996; Ross GD et al.
αMβ2/FcγRIIIB (CR3/CD16) alphaM-beta2 integrin complex Ross GD et al. ; Preynat-Seauve O et al. 2004; Sehgal G et al. 1993;
Zhou M et al. 1993
αMβ2/HP alphaM-beta2 integrin complex El-Ghmati SM et al. 2002
αMβ2/PR-3 alphaM-beta2 integrin complex David A et al. 2003
αMβ2/iC3b alphaM-beta2 integrin complex Gordon DL et al. 1987
αMβ2/ICAM[1,2,4] alphaM-beta2 integrin complex Diamond MS et al. 1990; Hermand P et al. 2000; Ross GD et al.
αMβ2/Talin-1 alphaM-beta2 integrin complex Lim J et al. 2007
αMβ2/Kindlin-3 alphaM-beta2 integrin complex
αMβ2/FUT4 (CR3/CD15) alphaM-beta2 integrin complex Skubitz KM and Snook RW 1987
αMβ2/RAGE alphaM-beta2 integrin complex Ma W et al.
αMβ2/RAGE/C1q alphaM-beta2 integrin complex Ma W et al.
αMβ2/CYR61(CCN1) alphaM-beta2 integrin complex Schober JM et al. 2002; Schober JM et al. 2003
αMβ2/CCN2 alphaM-beta2 integrin complex Schober JM et al. 2002
αMβ2/MPO alphaM-beta2 integrin complex El Kebir D et al. 2008; Johansson MW et al. 1997; Lau D et al. 2005
αMβ2/PLG alphaM-beta2 integrin complex Lishko VK et al. 2004
αMβ2/CyaA (B.pertussis) alphaM-beta2 integrin complex Guermonprez P et al. 2001
αMβ2/App1 (C. neoformans) alphaM-beta2 integrin complex Stano P et al. 2009
αMβ2/RrgA (S. pneumoniae) alphaM-beta2 integrin complex Orrskog S et al.
αMβ2/LPS (E.coli) alphaM-beta2 integrin complex Van Strijp JA et al. 1993; Ross GD et al. ; Wright SD and Jong MT
1986
αXβ2 (CR4, CD11c/18) alphaX-beta2 integrin complex Shelley CS et al. 2002; Lecoanet-Henchoz S et al. 1995
αXβ2/CD23 alphaX-beta2 integrin complex Lecoanet-Henchoz S et al. 1995
αXβ2/FUT4 (CR4/CD15) alphaX-beta2 integrin complex Skubitz KM and Snook RW 1987
αXβ2/Fibrinogen alphaX-beta2 integrin complex
αXβ2/iC3b alphaX-beta2 integrin complex Micklem KJ and Sim RB 1985; Chen X et al. 2012
αXβ2/ICAM-1 alphaX-beta2 integrin complex
αXβ2/LPS (E. coli) alphaX-beta2 integrin complex Ingalls RR and Golenbock DT 1995
αLβ2 (LFA-1, CD11a/18) alphaL-beta2 integrin complex
αLβ2/CD45 alphaL-beta2 integrin complex Geng X et al. 2005
αLβ2/CD47 alphaL-beta2 integrin complex Azcutia V et al. 2013
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αLβ2/CD82 alphaL-beta2 integrin complex Shibagaki N et al. 1999
αLβ2/Cytohesin-1 alphaL-beta2 integrin complex Kolanus W et al. 1996; Geiger C et al. 2000
αLβ2/ICAM[1-4] alphaL-beta2 integrin complex Edwards CP et al. 1998; Hermand P et al. 2000; Huang C and Springer
TA 1995; Li N et al. 2013; Mizuno T et al. 1997; Shimaoka M et al.
2001
αLβ2/RanBPM alphaL-beta2 integrin complex Denti S et al. 2004
αLβ2/DNAM-1 alphaL-beta2 integrin complex Shibuya K et al. 1999
αLβ2/JAB1 alphaL-beta2 integrin complex Bianchi E et al. 2000; Kinoshita SM et al.
αLβ2/FUT4 alphaL-beta2 integrin complex Skubitz KM and Snook RW 1987
αLβ2/ESM-1 alphaL-beta2 integrin complex Béchard D et al. 2001
αLβ2/Rack1 alphaL-beta2 integrin complex Liliental J and Chang DD 1998
αLβ2/VacA (H. pylori) alphaL-beta2 integrin complex Cover TL et al. 2008; Sewald X et al. 2008
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Volume 2,Issue 2, 2013 39

ACKNOWLEDGEMENTS
The UCSD Signaling Gateway Molecule Pages (SGMP) is
funded by NIH/NIGMS Grant 1 R01 GM078005-01. GH is
supported by NIH/NIDCR grants DE15254, DE17138,
DE21580, and DE21685. The authors thank Dr. John D.
Lambris, University of Pennsylvania School of Medicine,
Philadelphia, UCSD-SGMP editorial board member, for
extensive discussions.
SUPPLEMENTARY
Supplementary information is available online.
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MOLECULE PAGE
Volume 2,Issue 2, 2013 46

This molecule exists in 66 states , has 66 transitions between these states and has 0
enzyme functions.(Please zoom in the pdf file to view details.)
MOLECULE PAGE
Volume 2,Issue 2, 2013 47