The Leukocyte Integrins

polymorphonuclear leukocyte intercellular adhesion molecule metal ion-dependent adhesion site phosphatidylinositol protein kinase C pleckstrin homology focal adhesion kinase leukocyte adhesion deficiency type I 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 (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). 2The β2 integrins are comprehensively reviewed in Ref. 1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar. 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. 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 (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, 2Lorant D.E. Patel K.D. McIntyre T.M. McEver R.P. Prescott S.M. Zimmerman G.A. J. Cell Biol. 1991; 115: 223-234Crossref PubMed Scopus (545) Google Scholar, 3Rainger G.E. Buckley C. Simmons D.L. Nash G.B. Curr. Biol. 1997; 7: 316-325Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 4Feldhaus M.J. Kessel J.M. Zimmerman G.A. McIntyre T.M. J. Immunol. 1998; 161: 6280-6287PubMed Google Scholar, 5Campbell J.J. Hendrick K. Zlotnick A. Siani M.A. Thompson D.A. Butcher E.C. Science. 1998; 279: 381-384Crossref PubMed Scopus (844) Google Scholar, 6Johnston B. Burns A.R. Suematsu M. Issekutz T.B. Woodman R.C. Kubes P. J. Clin. Invest. 1999; 103: 1269-1276Crossref PubMed Scopus (170) Google Scholar). 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 β1, β2, and β7 integrins, but this varies with the subclass and is altered by immune stimulation (5Campbell J.J. Hendrick K. Zlotnick A. Siani M.A. Thompson D.A. Butcher E.C. Science. 1998; 279: 381-384Crossref PubMed Scopus (844) Google Scholar). Freshly isolated human monocytes express β1 and β2 integrins, but their culture and/or differentiation into macrophages changes the pattern and induces αvβ3 (5Campbell J.J. Hendrick K. Zlotnick A. Siani M.A. Thompson D.A. Butcher E.C. Science. 1998; 279: 381-384Crossref PubMed Scopus (844) Google Scholar, 7Krissansen G.W. Elliott M.J. Lucas C.M. Stomski F.C. Berndt M.C. Cheresh D.A. Lopez A.F. Burns G.F. J. Biol. Chem. 1990; 265: 823-830Abstract Full Text PDF PubMed Google Scholar). Human PMNs, once thought to express only β2 integrins, display β1 and β3 heterodimers and use them in motility and migration (8Bohnsack J.F. Akiyama S.K. Damsky C.H. Knape W.A. Zimmerman G.A. J. Exp. Med. 1990; 171: 1221-1237Crossref PubMed Scopus (113) Google Scholar, 9Kubes P. Niu X.F. Smith C.W. Kehrli Jr., M.E. Reinhardt P.H. Woodman R.C. FASEB J. 1995; 9: 1103-1111Crossref PubMed Scopus (169) Google Scholar, 10Hendey B. Lawson M. Marcantonio E.E. Maxfield F.R. Blood. 1996; 87: 2038-2048Crossref PubMed Google Scholar, 11Yauch R.L. Berditchevski F. Harler M.B. Reichner J. Hemler M.E. Mol. Biol. Cell. 1998; 9: 2751-2765Crossref PubMed Scopus (271) Google Scholar, 12Taooka Y. Chen J. Yednock T. Sheppard D. J. Cell Biol. 1999; 145: 413-420Crossref PubMed Scopus (241) Google Scholar). A common feature, however, is that each leukocyte subtype expresses one or more members of the β2 integrin family. Further, the β2 heterodimers are restricted to cells of the leukocyte lineage. The remainder of this minireview will focus on the structure and function of the β2 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, αDβ2, 3The designations for the β2integrin 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 αLβ2, αMβ2, and αXβ2, respectively, and are still often used. αMβ2 integrin was also earlier called MO-1 and complement receptor 3 (CR3). The CD designations for the individual subunits are CD11a (αL), CD11b (αM), CD11c (αX), and CD18 (β2). The αDchain will likely be assigned as CD11d (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). is still being characterized (13Danilenko D.M. Rossitto P.V. Van der Vieren M. Le Trong H. McDonough S.P. Affolter V.K. Moore P.F. J. Immunol. 1995; 155: 35-44PubMed Google Scholar, 14Van der Vieren M. Le Trong H. Wood C.L. Moore P.F. St. John T. Staunton D.E. Gallatin W.M. Immunity. 1995; 3: 683-690Abstract Full Text PDF PubMed Scopus (234) Google Scholar, 15Grayson M.H. Van der Vieren M. Sterbinsky S.A. Gallatin W.M. Hoffman P.A. Staunton D.E. Bochner B.S. J. Exp. Med. 1998; 188: 2187-2191Crossref PubMed Scopus (112) Google Scholar, 16Van der Vieren M. Crowe D.T. Hoekstra D. Vazeux R. Hoffman P.A. Grayson M.H. Bochner B.S. Gallatin W.M. Staunton D.E. J. Immunol. 1999; 163: 1984-1990PubMed Google Scholar). The gene for the β2 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 β2, including four repeated cysteine motifs, is conserved in the β1, β2, and β3 integrin chains and may be important for a rigid tertiary structure. The extracellular portion of β2 contains a 241-amino acid “I-like” domain near the N terminus (Fig. 1) that is highly conserved in other β subunits and is critical for ligand recognition (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 18Goodman T.G. Bajt M.L. J. Biol. Chem. 1996; 271: 23729-23736Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar) (see below). The genes for human αL (M r177,000), αM (M r 165,000), αX (M r 150,000), and αD (M r 160,000) are located in a cluster on chromosome 16 (19Wong D.A. Davis E.M. LeBeau M. Springer T.A. Gene (Amst.). 1996; 171: 291-294Crossref PubMed Scopus (19) Google Scholar). Their sequences are similar with αM, αX, and αD having 60–66% amino acid identity and sharing 35% identity with αL. 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 (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 20Springer T.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 65-72Crossref PubMed Scopus (393) Google Scholar). I domains are also present in α1, α2, and αE. The N-terminal extracellular regions of the α subunits include seven repeats that fold into a β 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 β2 subunit (20Springer T.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 65-72Crossref PubMed Scopus (393) Google Scholar). The cytoplasmic tails of the α chains are constitutively phosphorylated in some leukocyte types, but the contribution of phosphorylation to function is unclear (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). The membrane-proximal cytoplasmic domains of each α chain contain a GFFKR motif common to all integrin α 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 α/β subunit association (21Hughes P.E. Diaz-Gonzalez F. Leong L. Wu C. McDonald J.A. Shattil S.J. Ginsberg M.H. J. Biol. Chem. 1996; 271: 6571-6574Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar). The factors that dictate leukocyte-specific expression of the α and β chains remain incompletely defined (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). In myeloid leukocyte subtypes, specific β2 heterodimers are differentially targeted to subcellular storage granules in addition to the plasma membrane. Cellular activation then leads to translocation of granular β2 heterodimers to the surface. Activation of constitutive surface β2 integrins can occur without translocation of additional heterodimers from granules; treatment of neutrophils with ceramide or cytochalasins dissociates these two events (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, 4Feldhaus M.J. Kessel J.M. Zimmerman G.A. McIntyre T.M. J. Immunol. 1998; 161: 6280-6287PubMed Google Scholar). 4M. Feldhaus, G. A. Zimmerman, and T. M. McIntyre, submitted for publication. There is differential activation of constitutive surface and newly translocated β2 integrins on migrating PMNs and redistribution of heterodimers to specialized regions of the plasma membrane (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, 22Hughes B.J. Hollers J.C. Crockett-Torabi E. Smith C.W. J. Clin. Invest. 1992; 90: 1687-1696Crossref PubMed Scopus (164) Google Scholar). β2 integrins dynamically associate with other plasma membrane proteins. These interactions alter adhesive and signaling functions (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar) (see the last minireview in this series by Woods and Couchman (83Woods A. Couchman J.R. J. Biol. Chem. 2000; 275: 24233-24236Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar)). Each of the β2 integrins recognizes one or more members of the intercellular adhesion molecule (ICAM) family. αMβ2, αXβ2, and αDβ2 also recognize proteins of other classes and (in the case of αMβ2 and αXβ2) 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 (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar). The RGD motif, which is a critical feature in many integrin ligands, is not a required feature in ligands for β2 heterodimers. The crystal structures of the I domains of αM and αL have been solved (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 23Qu A. Leahy D.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10277-10281Crossref PubMed Scopus (291) Google Scholar), providing rosetta stones for general understanding of integrin structure-function relationships. The crystal structure of the I domain of αM 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 (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 24Michishita M. Videm V. Arnaout M.A. Cell. 1993; 72: 857-867Abstract Full Text PDF PubMed Scopus (346) Google Scholar) (Fig. 1). Blocking and mutagenesis of the metal coordinating sites in the MIDAS motifs of α subunits alter or abolish ligand binding, as does mutagenesis of key residues in the flanking regions.2A DXSXS motif is also found in the I-like domain of the β2 subunit. Its mutation eliminates ligand recognition (17Lee J.O. Rieu P. Arnaout M.A. Liddington R. Cell. 1995; 80: 631-638Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 18Goodman T.G. Bajt M.L. J. Biol. Chem. 1996; 271: 23729-23736Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 25Bajt M.L. Goodman T. McGuire S.L. J. Biol. Chem. 1995; 270: 94-98Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Changes in tertiary conformation of the α I domains may be a general mechanism that dictates active and inactive states of the β2 integrins (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). The crystal I domain of αM 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 αL were grown under various ionic conditions (23Qu A. Leahy D.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10277-10281Crossref PubMed Scopus (291) Google Scholar, 26Lee J.O. Bankston L.A. Arnaout M.A. Liddington R.C. Structure. 1995; 3: 1333-1340Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 27Li R. Rieu P. Griffith D.L. Scott D. Amin Arnaout M. J. Cell Biol. 1998; 143: 1523-1534Crossref PubMed Scopus (124) Google Scholar). Quaternary structural alterations likely also occur. One model proposes that the β subunit I-like domain folds over the α subunit propeller in the low affinity unactivated state, blocking the α I domain and its central MIDAS motif (Fig. 1). Quaternary changes triggered by inside-out signals (see below) shift the β chain I-like domain, exposing the α subunit I domain and other ligand recognition sites in the α propeller in concert with simultaneous conversion of the α subunit I domain to an active conformation via tertiary changes (28Loftus J.C. Liddington R.C. J. Clin. Invest. 1997; 99: 2302-2306Crossref PubMed Google Scholar). Thus, dynamic structural alterations in β2 heterodimers are involved in ligand recognition, as with other classes of integrins (see the first minireview in this series by Plow et al.(84Plow E.F. Haas T.A. Zhang L. Loftus J. Smith J.W. J. Biol. Chem. 2000; 275: 21785-21788Abstract Full Text Full Text PDF PubMed Scopus (1144) Google Scholar)). Modulation of avidity is also involved (see below). Activation of leukocytes by agonists that bind to diverse classes of receptors triggers ligand recognition by β2 integrins. This process is termed “inside-out signaling,” integrin “activation,” and “functional up-regulation” (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). 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 (85Calderwood D.A. Shattil S.J. Ginsberg M.H. J. Biol. Chem. 2000; 275: 22607-22610Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar)). More than one pathway may trigger inside-out signaling of an individual β2 integrin heterodimer (29Jones S.L. Knaus U.G. Bokoch G.M. Brown E.J. J. Biol. Chem. 1998; 273: 10556-10566Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 30Weber K.S. Klickstein L.B. Weber C. Mol. Biol. Cell. 1999; 10: 861-873Crossref PubMed Scopus (82) Google Scholar). Transfected and mutated cell systems are now popular for analysis of integrin signaling (30Weber K.S. Klickstein L.B. Weber C. Mol. Biol. Cell. 1999; 10: 861-873Crossref PubMed Scopus (82) Google Scholar, 31Baker E.K. Tozer E.C. Pfaff M. Shattil S.J. Loftus J.C. Ginsberg M.H. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1973-1978Crossref PubMed Scopus (67) Google Scholar, 32Romzek N.C. Harris E.S. Dell C.L. Skronek J. Hasse E. Reynolds P.J. Hunt III, S.W. Shimizu Y. Mol. Biol. Cell. 1998; 9: 2715-2727Crossref PubMed Scopus (40) Google Scholar). Such models suggest that inside-out signaling of β2 integrins occurs via mechanisms dependent on the small GTPase Rho (33Laudanna C. Campbell J.J. Butcher E.C. Science. 1996; 271: 981-983Crossref PubMed Scopus (435) Google Scholar, 34Laudanna C. Campbell J.J. Butcher E.C. J. Biol. Chem. 1997; 272: 24141-24144Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar) and that there is differential intracellular regulation of the activity of β2 versusβ1, β3, and β7 integrins in the same transfected cell type (35Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 36Lub M. van Vliet S.J. Oomen S.P. Pieters R.A. Robinson M. Figdor C.G. van Kooyk Y. Mol. Biol. Cell. 1997; 8: 719-728Crossref PubMed Scopus (46) Google Scholar, 37Sadhu C. Masinovsky B. Staunton D.E. J. Immunol. 1998; 160: 5622-5628PubMed Google Scholar). There are cell-specific aspects of integrin regulation, however, that may operate in model cell systems but not in primary leukocytes and vice versa (38Hibbs M.L. Jakes S. Stacker S.A. Wallace R.W. Springer T.A. J. Exp. Med. 1991; 174: 1227-1238Crossref PubMed Scopus (213) Google Scholar). Analysis of inside-out signaling of β2 integrins is most detailed for αLβ2. 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 occur on lymphocytes E.M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar) and other leukocytes (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar). of the of and induces rapid dynamic changes in recognition of and other ligands (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, L. L. Springer T.A. J. Immunol. 1998; 160: Google Scholar). with on the I domain of αL that this is required for recognition when to the high affinity state on T cells with A. B. P. P.A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In treatment of T cells with or that intracellular of and avidity of binding without change in affinity A. B. P. P.A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, Kooyk Y. P. K. Figdor C.G. J. Cell Biol. PubMed Scopus Google Scholar, C. J. Immunol. 1996; Google Scholar, A. J. Cell Biol. 1998; PubMed Scopus Google Scholar). of in the plasma of is by and by that conversion from the non-adhesive to the adhesive state signals that alter cytoskeletal interactions and allow the integrin to into or adhesive M.L. J.M. Brown E.J. J. Clin. Invest. 1996; PubMed Scopus Google Scholar). of membrane occurs in and T cells and adhesion to K. P. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). There is additional for avidity modulation of in cell models K. J. Exp. Med. 1995; PubMed Scopus Google Scholar, Kooyk Y. van Vliet S.J. Figdor C.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of in the of contact occurs in T cells to cellular or proteins in model M.L. J. S. P. F. van der P.A. Cell. 1998; 94: Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. 1998; PubMed Scopus Google Scholar). regulation of affinity avidity of triggered by specific signals and may a mechanism in which which can be by and by other binding and altered avidity occur in sequence A. B. P. P.A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, Kooyk Y. van Vliet S.J. Figdor C.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). and of the GFFKR motif of αL (Fig. 1) in a T cell and in constitutive there is also additional that the membrane-proximal of the α cytoplasmic tail a general effect on ligand recognition that is of the β chain (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, P.E. Diaz-Gonzalez F. Leong L. Wu C. McDonald J.A. Shattil S.J. Ginsberg M.H. J. Biol. Chem. 1996; 271: 6571-6574Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 30Weber K.S. Klickstein L.B. Weber C. Mol. Biol. Cell. 1999; 10: 861-873Crossref PubMed Scopus (82) Google Scholar, Springer T.A. J. Immunol. 1997; Google Scholar). The β2 cytoplasmic tail however, critical for modulation of adhesiveness (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, M.L. Jakes S. Stacker S.A. Wallace R.W. Springer T.A. J. Exp. Med. 1991; 174: 1227-1238Crossref PubMed Scopus (213) Google Scholar, K. J. Exp. Med. 1995; PubMed Scopus Google Scholar, Springer T.A. J. Immunol. 1997; Google Scholar). The β2 chain with a of cytoskeletal and including and of these interactions have been to be altered when leukocytes of classes are by and to function (1Kishimoto T.K. Baldwin E.T. Anderson D.C. Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. 3rd Ed. Lippincott Williams and Wilkins, Philadelphia1999: 537-570Google Scholar, R. P.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). signaling of on cells is regulated by Rho downstream of protein kinase C T. K. M. J. A. H. S. J. Cell Biol. 1993; PubMed Scopus Google Scholar), with in transfected cells and integrins are reviewed in and Seed W. Seed B. Curr. Cell Biol. 1997; 9: PubMed Scopus Google Scholar). A member of the in and cell (35Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, W. Zeitlmann L. P. C. J. W. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, W. P. Zeitlmann L. W. Mol. Biol. Cell. 1998; 9: PubMed Scopus Google Scholar, P. D. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (87) Google Scholar). was identified the intracellular domain of β2 in a a pleckstrin homology domain and an N-terminal motif similar to the domain, membrane association and activity (35Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, W. Zeitlmann L. P. C. J. W. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). with in of a T cell but not with (35Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar). of or its motif in cells adhesion to without on the of the domain adhesion by T cell receptor (35Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar). of a constitutively active phosphatidylinositol adhesion of cells to and membrane association of both of which were by of the domain but not by a motif W. Zeitlmann L. P. C. J. W. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). This that of to the plasma membrane the domain where inside-out signaling of αLβ2, via the domain W. Zeitlmann L. P. C. J. W. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, P. D.