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J. Biol. Chem., Vol. 275, Issue 31, 23409-23412, August 4, 2000

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MINIREVIEW
The Leukocyte Integrins^*

Estelle S. Harris^§, Thomas M. McIntyre^§¶, Stephen M. Prescott^**, and Guy A. Zimmerman^§

From the ^§ Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, ^** Huntsman Cancer Institute, and Departments of  Internal Medicine,  Oncologic Sciences, and ^¶ Pathology, University of Utah, Salt Lake City, Utah 84112

	Integrins on Leukocytes

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Leukocytes are marrow-derived cells of diverse form and function that circulate in the blood in a quiescent state of low adhesiveness before migrating into tissues to defend against invading microbes, participate in immune functions and wound repair, or become fixed extracellular residents. Some, such as T-lymphocytes, recirculate and traverse blood, organ, and lymphatic compartments during long cycles of immune surveillance. Others, notably polymorphonuclear leukocytes (PMNs,¹ neutrophils), are rapid response cells specialized for acute spatially targeted defensive actions that can be mounted in minutes. Leukocytes are also effectors of pathologic inflammation when their accumulation and actions are disregulated. Integrins on their surfaces, together with other plasma membrane adhesion molecules, are required for interactions of leukocytes with endothelial cells and other cell types and with matrix structures (1).² The functional state, density, and topography of integrins on leukocytes are regulated by lipid, cytokine, and chemokine signaling molecules and by "cross-talk" from other surface adhesion molecules (1-6).

Each class of leukocytes displays a particular pattern of integrins that can change in a signal- and time-dependent fashion. For example, resting human T lymphocytes (T cells) express ₁, ₂, and ₇ integrins, but this varies with the subclass and is altered by immune stimulation (5). Freshly isolated human monocytes express ₁ and ₂ integrins, but their culture and/or differentiation into macrophages changes the pattern and induces _v3 (5, 7). Human PMNs, once thought to express only ₂ integrins, display ₁ and ₃ heterodimers and use them in motility and migration (8-12). A common feature, however, is that each leukocyte subtype expresses one or more members of the ₂ integrin family. Further, the ₂ heterodimers are restricted to cells of the leukocyte lineage. The remainder of this minireview will focus on the structure and function of the ₂ or "leukocyte" integrins, which were among the first adhesion molecules to be studied at the molecular level. The most recently identified member of the subfamily, _D2,³ is still being characterized (13-16).

	Structure and Distribution

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

The gene for the ₂ chain (M_r 95,000) is located in band q22 on human chromosome 21 and encodes a cysteine-rich transmembrane protein with six N-linked extracellular glycosylation sites. The cytoplasmic tail contains sequences critical for inside-out signaling and cytoskeletal association. Cytoplasmic residues are differentially phosphorylated in an agonist-dependent fashion in neutrophils, but the effect on adhesive function is not clear. Each of 56 cysteine residues in ₂, including four repeated cysteine motifs, is conserved in the ₁, ₂, and ₃ integrin chains and may be important for a rigid tertiary structure. The extracellular portion of ₂ contains a 241-amino acid "I-like" domain near the N terminus (Fig. 1) that is highly conserved in other  subunits and is critical for ligand recognition (17, 18) (see below).

View larger version (30K): [in this window] [in a new window]   Fig. 1.   Features of 2 integrins. The heterodimeric structure is common to all integrins. The  chain includes seven extracellular N-terminal homologous repeats organized into a  propeller structure. The  chain I domain is shown in pink with the embedded MIDAS motif in orange, and the  chain I-like domain with MIDAS motif is shown in corresponding fashion. The GFFKR sequence (green) in the cytoplasmic tail of the  subunit is involved in heterodimer assembly and regulation of ligand recognition. The heterodimer is illustrated in the "closed" or inactive state that undergoes tertiary and quaternary changes in response to inside-out signals. See "Structure and Distribution," "Ligand Recognition," and "Inside-out Signaling" for details.

The genes for human _L (M_r 177,000), _M (M_r 165,000), _X (M_r 150,000), and _D (M_r 160,000) are located in a cluster on chromosome 16 (19). Their sequences are similar with _M, _X, and _D having 60-66% amino acid identity and sharing 35% identity with _L. Each contains a distal N-terminal extracellular "I domain" (signifying "inserted" or "interactive"; also called the "A domain" because of homology to the A motif in von Willebrand factor) of approximately 200 amino acids that is critical for ligand binding (17, 20). I domains are also present in ₁, ₂, and _E. The N-terminal extracellular regions of the  subunits include seven repeats that fold into a  propeller configuration. The I domains lie within the third repeat (Fig. 1) and are predicted to be exposed and mobile. The three membrane-proximal N-terminal repeats resemble EF hand Ca²⁺-binding motifs and are situated on the lower face of the propeller away from the ligand contact sites, where they may contribute to orientation of the propeller and/or to interaction with the ₂ subunit (20).

The cytoplasmic tails of the  chains are constitutively phosphorylated in some leukocyte types, but the contribution of phosphorylation to function is unclear (1). The membrane-proximal cytoplasmic domains of each  chain contain a GFFKR motif common to all integrin  subunits that putatively serves as a "hinge" that locks the heterodimers into a low affinity conformation in the absence of activating signals and is involved in / subunit association (21).

The factors that dictate leukocyte-specific expression of the  and  chains remain incompletely defined (1). In myeloid leukocyte subtypes, specific ₂ heterodimers are differentially targeted to subcellular storage granules in addition to the plasma membrane. Cellular activation then leads to translocation of granular ₂ heterodimers to the surface. Activation of constitutive surface ₂ integrins can occur without translocation of additional heterodimers from granules; treatment of neutrophils with ceramide or cytochalasins dissociates these two events (1, 4).⁴ There is differential activation of constitutive surface and newly translocated ₂ integrins on migrating PMNs and redistribution of heterodimers to specialized regions of the plasma membrane (1, 22). ₂ integrins dynamically associate with other plasma membrane proteins. These interactions alter adhesive and signaling functions (1) (see the last minireview in this series by Woods and Couchman (83)).

	Ligands

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Each of the ₂ integrins recognizes one or more members of the intercellular adhesion molecule (ICAM) family. _M2, _X2, and _D2 also recognize proteins of other classes and (in the case of _M2 and _X2) polysaccharides. The unifying feature of protein ligands may be the presence of acidic residues (aspartate or glutamate) positioned in flexible loops that allow them to coordinate Mg²⁺ or Mn²⁺ and form a bridge to the I and/or I-like domains on the integrin heterodimer (17). The RGD motif, which is a critical feature in many integrin ligands, is not a required feature in ligands for ₂ heterodimers.

	Ligand Recognition

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

The crystal structures of the I domains of _M and _L have been solved (17, 23), providing rosetta stones for general understanding of integrin structure-function relationships. The crystal structure of the I domain of _M reveals a coordination locus for Mg²⁺ and Mn²⁺ that is proposed as a general "metal ion-dependent adhesion site" (MIDAS) consisting of the sequence DXSXS together with downstream non-contiguous Asp and Thr residues (17, 24) (Fig. 1). Blocking and mutagenesis of the metal coordinating sites in the MIDAS motifs of  subunits alter or abolish ligand binding, as does mutagenesis of key residues in the flanking regions.² A DXSXS motif is also found in the I-like domain of the ₂ subunit. Its mutation eliminates ligand recognition (17, 18, 25).

Changes in tertiary conformation of the  I domains may be a general mechanism that dictates active and inactive states of the ₂ integrins (1). The crystal I domain of _M assumes two conformations, an open or "active" and a closed or "inactive" structure, that differentially recognize ligands although conformational alterations were not seen when crystals of the I domain of _L were grown under various ionic conditions (23, 26, 27). Quaternary structural alterations likely also occur. One model proposes that the  subunit I-like domain folds over the  subunit propeller in the low affinity unactivated state, blocking the  I domain and its central MIDAS motif (Fig. 1). Quaternary changes triggered by inside-out signals (see below) shift the  chain I-like domain, exposing the  subunit I domain and other ligand recognition sites in the  propeller in concert with simultaneous conversion of the  subunit I domain to an active conformation via tertiary changes (28). Thus, dynamic structural alterations in ₂ heterodimers are involved in ligand recognition, as with other classes of integrins (see the first minireview in this series by Plow et al. (84)). Modulation of avidity is also involved (see below).

	Inside-out Signaling

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Activation of leukocytes by agonists that bind to diverse classes of receptors triggers ligand recognition by ₂ integrins. This process is termed "inside-out signaling," integrin "activation," and "functional up-regulation" (1). Rapid, regulated modulation of ligand recognition is critical for leukocytes, because they must circulate in a non-adhesive state before targeting and arrest at specific sites. The molecular mechanisms that mediate inside-out signaling of integrins have been elusive (see the second minireview in this series by Ginsburg and co-workers (85)). More than one pathway may trigger inside-out signaling of an individual ₂ integrin heterodimer (29, 30). Transfected and mutated cell systems are now popular for analysis of integrin signaling (30-32). Such models suggest that inside-out signaling of ₂ integrins occurs via mechanisms dependent on the small GTPase Rho (33, 34) and that there is differential intracellular regulation of the activity of ₂ versus ₁, ₃, and ₇ integrins in the same transfected cell type (35-37). There are cell-specific aspects of integrin regulation, however, that may operate in model cell systems but not in primary leukocytes and vice versa (38).

Analysis of inside-out signaling of ₂ integrins is most detailed for _L2. Changes in both affinity and avidity are involved, depending in part on the cellular system and the stimulus chosen to alter its adhesive function. Low and high affinity states of _L2 occur on lymphocytes (39) and other leukocytes (1). Manipulation of the "extracellular face" of _L2 using divalent cations and function-perturbing antibodies induces rapid dynamic changes in recognition of ICAM-1 and other ligands (1, 40). Recent experiments with soluble recombinant peptides based on the I domain of _L indicate that this region is required for ICAM-1 recognition when _L2 shifts to the high affinity state on cultured T cells treated with Mg²⁺ (41). In contrast, treatment of T cells with phorbol esters or agents that increase intracellular Ca²⁺ causes clustering of _L2 and increased avidity of binding without detectable change in affinity (41-44). Lateral motion of _L2 in the plasma membranes of Epstein-Barr virus-transformed lymphoblasts is enhanced by phorbol esters and by cytochalasins, suggesting that conversion from the non-adhesive to the adhesive state involves signals that alter cytoskeletal interactions and allow the integrin to segregate into clusters or adhesive patches (45). Clustering of membrane "rafts" containing _L2 occurs in murine thymocytes and activated T cells and confers adhesion to ICAM-1 (46). There is additional evidence for avidity modulation of _L2 in surrogate cell models (47, 48). Lateral segregation of _L2 in the plane of contact occurs in T cells adherent to cellular targets or purified proteins in model membranes (49, 50). Differential regulation of affinity versus avidity of _L2 is triggered by specific signals and may involve a two-step mechanism in which increased affinity, which can be induced by ICAM-1 and potentially by other binding partners, and altered avidity occur in sequence (41, 48).

Truncations, mutations, and deletions of the GFFKR motif of _L (Fig. 1) in a Jurkat T cell line and in K562 transfectants cause constitutive ICAM-1 recognition; there is also additional evidence that the membrane-proximal region of the  cytoplasmic tail exerts a general inhibitory effect on ligand recognition that is independent of the  chain (1, 21, 30, 51). The ₂ cytoplasmic tail is, however, critical for modulation of _L2 adhesiveness (1, 38, 47, 51). The ₂ chain associates with a variety of cytoskeletal and regulatory proteins, including -actinin, talin, filamin, vinculin, and Rack 1. Certain of these interactions have been demonstrated to be altered when leukocytes of different classes are activated by physiologically relevant stimuli and to regulate _L2 function (1, 52). Inside-out signaling of _L2 on B lymphoblastoid cells is regulated by Rho acting downstream of protein kinase C (PKC) (53), consistent with studies in transfected cells mentioned above.⁵

A member of the Sec7 family, cytohesin-1, modulates _L2 in lymphocytic and monocytic cell lines (35, 54-56). Cytohesin-1 was identified using the intracellular domain of ₂ in a yeast two-hybrid screen; it has a C-terminal pleckstrin homology (PH) domain and an N-terminal motif similar to the yeast Sec7 domain, conferring membrane association and guanine nucleotide exchange factor activity (35, 54). Cytohesin-1 weakly coimmunoprecipitated with _L2 in lysates of a Jurkat T cell line, but not with ₄₁ (35). Overexpression of cytohesin-1 or its Sec7 motif in Jurkat cells induced _L2-dependent adhesion to immobilized ICAM-1 without increasing _L2 heterodimers on the surface, whereas overexpression of the PH domain inhibited adhesion stimulated by T cell receptor engagement (35). Expression of a constitutively active chimeric phosphatidylinositol 3-kinase (PI 3-kinase) induced adhesion of Jurkat cells to ICAM-1 and increased membrane association of cytohesin-1, both of which were inhibited by overexpression of the PH domain but not by a control PH motif (54). This suggests that PI 3-kinase regulates recruitment of cytohesin-1 to the plasma membrane utilizing the PH domain where it mediates inside-out signaling of _L2, potentially via the Sec7 domain (54, 56). Additional evidence in other systems indicates that signals delivered via PI 3-kinases activate integrins, potentially converging with signals from PKC.^2,5 It is unknown if inside-out signaling of _L2 on primary leukocytes is mediated by PI 3-kinase-dependent cytohesin-1 translocation. A recently identified factor that is structurally similar to cytohesin-1, GRP1, also regulates _L2 in leukocyte cell lines (57).

Inside-out signaling and ligand recognition of _M2 follows paradigms outlined for _L2 (1, 26-29). Two functional states of the crystallized _M I domain indicate a basis for changes in conformation (17, 26, 27). Avidity modulation involving clustering of _M2 or cell spreading also occurs (1, 29, 30, 58). L-plastin, an actin-organizing protein, regulates _M2 on human monocytes and neutrophils based on experiments with cell-permeant peptides (59). In human neutrophils, inside-out signaling of _M2 was dependent on PI 3-kinase and actin cytoskeletal reorganization when triggered by engagement of Fc receptors but not when the leukocytes were activated through the receptors for inflammatory peptides (29). An inhibitor of PI 3-kinase also failed to block _M2-dependent adhesive interactions of neutrophils in earlier experiments (60). These findings are consistent with differential regulation of _M2 and _L2 via the  cytoplasmic tails (30) and also suggest alternative mechanisms for signaling of cytohesin-1 interaction with the cytoplasmic tail of ₂ if it is central to activation of _M2, as proposed for _L2 (see above). Pak1, a serine/threonine kinase, may be an intermediary in a pathway leading to inside-out signaling of _M2 in neutrophils (29).

	Outside-in Signaling

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Engagement of integrins delivers outside-in signals that trigger intracellular transduction cascades, in addition to mediating adhesion. These outside-in signals can also be integrated with signals delivered through receptors for signaling molecules to yield coordinated functional responses. Cross-linking of leukocyte integrins with antibodies against ₂ or specific  subunits, engagement of ₂ heterodimers with specific ligands, or coengagement of ₂ integrins together with other surface structures or receptors delivers outside-in signals that lead to diverse cellular responses (1).² Signaling to gene regulatory pathways involves transcriptional events and mRNA stabilization and is differentially affected by experimental conditions when ₁ versus ₂ integrins are engaged (61-64). Outside-in signaling by specific ₂ integrins may vary in leukocyte subtypes (65) and is impaired in leukocytes from subjects with leukocyte adhesion deficiency type I (LAD I) (see below) (66, 67).

Several intracellular signaling pathways are triggered by engagement of ₂ integrins (1). Activation of focal adhesion kinase (FAK) is central to many paradigms of outside-in signaling by integrins, and FAK binds peptides based on the sequence of the ₂ cytoplasmic domain in addition to ₁ and ₃ cytoplasmic peptides (68). Nevertheless, FAK does not appear to be critical for outside-in signaling by ₂ integrins, and it is inconsistently detected in human monocytes and neutrophils (63, 69) even though phosphorylation on tyrosine occurs in these cells in response to ₂ integrin engagement (1, 67). In contrast, the human THP-1 monocytic leukemia cell does express FAK (70), illustrating the potential differences in integrin signaling in primary leukocytes versus transformed cell lines.

Integrin-linked kinase, a serine/threonine kinase that associates with ₁ cytoplasmic domains, and calreticulin, which associates with the GFFKR sequence of  subunits, mediate signaling functions of integrins (71, 72), but it is not known if they regulate ₂ heterodimers.

	Genetically Altered Animal Models

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Mice with partial (73) and complete (74) deficiency of ₂ integrins and specific deletions of _L2 (75), _M2 (76, 77), and _D2⁶ have been produced. Animals deficient in all ₂ integrins display phenotypic features of humans with LAD I (see below) including neutrophilia and a defect in accumulation of PMNs in inflamed skin. PMN emigration into lung alveoli in response to a bacterial challenge and into the peritoneum in response to a sterile irritant are preserved (74). Blocking antibodies against ₂ integrins inhibit neutrophil accumulation under the same or similar conditions (1, 74), however, suggesting alternative adhesion mechanisms that compensate for deficiency of ₂ integrins in mice. In contrast, absence of PMNs from inflamed or injured extravascular sites is the usual outcome in most humans with ₂ integrin deficiency (1).

Individual knockouts of _L2 and _M2 yielded surprises, including the fact that PMNs efficiently use _L2 for emigration in mice null for _M2 (77). This was unexpected, because the diversity of ligands recognized by _M2 relative to _L2 (1) suggested that it would be required for traversing complex tissue compartments. Integrins _X2 and/or _D2 may substitute for _M2, together with ₁ integrins (1, 8-16). In inflammatory disease models neutrophil effector functions are impaired in mice lacking _M2 (77, 78), potentially because of absent outside-in signaling or deficient signal integration (see above). One of these models indicated interaction between _M2 and Fc receptors (78), which was predicted by earlier in vitro observations (1). The same strain of mice was deficient in tissue mast cells, indicating that _M2 is important in targeting and/or development of this extravascular leukocyte subtype (79).

	LAD I and LAD I Variant Syndromes

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

Humans with LAD I have absent or a greatly reduced display of all ₂ integrin heterodimers on the surfaces of their leukocytes, absent or dramatically reduced accumulation of PMNs and monocytes at extravascular sites, recurrent life-threatening bacterial infections, and impaired tissue remodeling and wound healing. Cells from these subjects have defective adhesive and signaling functions when studied in vitro (1, 2, 66, 67). The search for the molecular basis of LAD I led to identification and initial characterization of ₂ integrins (1). The syndrome results from a variety of mutations that prevent normal heterodimer formation and surface display. Recently, variant LAD I syndromes have been identified (80, 81).⁷ Each of these subjects had clinical features consistent with LAD I but, in contrast to the phenotype outlined above, had normal or only moderately reduced levels of ₂ integrins (40-60% of control) on the surfaces of circulating leukocytes at the time of diagnosis. In one of the subjects there were two new mutations of the  chain; one was located in the MIDAS motif of the I-like domain (81). Phenotypic and sequence characterization of leukocytes from the other two subjects indicates a defect in inside-out signaling. These rare LAD variants, like variations in structure and signaling of integrin _IIb3 in the syndrome of Glanzmann thrombasthenia (82), may yield unique insights that are relevant both to ₂ heterodimers on leukocytes and to the biology of integrins in general.

	ACKNOWLEDGEMENTS

We thank Takashi Kei Kishimoto and Nancy Hogg for making unpublished manuscripts available to us, John McDonald for editorial comments, Michelle Bills and Diana Lim for preparation of the manuscript and figure, and the members of our group and many other colleagues for useful discussions and other contributions.

	FOOTNOTES

^* This minireview will be reprinted in the 2000 Minireview Compendium, which will be available in December, 2000. This is the third article of four in the "Integrin Minireview Series." This work was supported by National Institutes of Health Grants HL44525, K08 HL03799, CA59548, and P50 HL50153, an Asthma Research Center funded by the American Lung Association, the Eccles Program in Human Molecular Biology and Genetics, and the Huntsman Cancer Foundation.

To whom correspondence should be addressed: Program in Human Molecular Biology and Genetics, Suite 4220, Eccles Inst. of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, UT 84112. Tel.: 801-585-0727; Fax: 801-585-0701; E-mail: guy.zimmerman@hmbg.utah.edu.

Published, JBC Papers in Press, May 4, 2000, DOI 10.1074/jbc.R000004200

² The ₂ integrins are comprehensively reviewed in Ref. 1. In the last decade dozens of reviews and hundreds of primary reports on leukocyte function, leukocyte integrins, and specific aspects of the biology of integrins have appeared. We used many that could not be cited because of space limitations and will provide a list of these on request.

³ The designations for the ₂ integrin heterodimers and their individual peptide subunits can be confusing. The trivial names LFA-1, MAC-1, and GP150,95 antedated the more recent designations of _L2, _M2, and _X2, respectively, and are still often used. _M2 integrin was also earlier called MO-1 and complement receptor 3 (CR3). The CD designations for the individual subunits are CD11a (_L), CD11b (_M), CD11c (_X), and CD18 (₂). The _D chain will likely be assigned as CD11d (1).

⁴ M. Feldhaus, G. A. Zimmerman, and T. M. McIntyre, submitted for publication.

⁵ PI 3-kinases, PKC, and integrins are reviewed in Kolanus and Seed (86).

⁶ M. Bunting, T. M. McIntyre, S. M. Prescott, and G. A. Zimmerman, unpublished observations.

⁷ E. S. Harris, A. D. Shigedka, W. Li, R. H. Adams, S. M. Prescott, T. M. McIntyre, G. A. Zimmerman, and D. E. Lorant, submitted for publication.

	ABBREVIATIONS

The abbreviations used are: PMN, polymorphonuclear leukocyte; ICAM, intercellular adhesion molecule; MIDAS, metal ion-dependent adhesion site; PI, phosphatidylinositol; PKC, protein kinase C; PH, pleckstrin homology; FAK, focal adhesion kinase; LAD I, leukocyte adhesion deficiency type I.

	REFERENCES

TOP Integrins on Leukocytes Structure and Distribution Ligands Ligand Recognition Inside-out Signaling Outside-in Signaling Genetically Altered Animal... LAD I and LAD... REFERENCES

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