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Integrin signaling
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Integrin Signa[ing KENNETH M. YAMADA Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD, USA
Abstract Integrins provide dynamic links between cells and extracellular matrix molecules. Although integrins were originally viewed as relatively simple adhesion molecules, it soon became clear that intracellular signal transduction initiated by integrins is centrally involved in many cellular processes. In fact, a remarkable number of classical signaling pathways are now known to be activated or modified by the interactions of cells with matrix proteins via integrins. These integrin signaling responses can also involve many other extracellular and intracellular molecules. The following mini-reviews were solicited from some of the future leaders in the field of integrin signaling. They examine selected important portions of this field, provide conceptual syntheses from a large and confusing literature, and then propose novel testable ideas. These ideas should encourage dialogue and open new avenues of research in this rapidly expanding, exciting field. Key words: cell adhesion, cytoskeleton, extracellular matrix, integrin, signal transduction.
Introduction Integrins mediate both adhesion and bi-directional information transfer (Figure 1). Signaling information originating from binding interactions between integrins and extraceilular matrix molecules (ligands) is transduced across the plasma membrane into a variety of signal transduction pathways in a process termed "outsidein" signaling. In addition, however, intracellular regulators modify external integrin ligand-binding properties in a process termed "inside-out" signaling. There are many outstanding reviews in this field. A sampling from the >100 reviews on integrin signaling published in just the past couple of years include the following 3 dozen general reviews of various aspects of this dynamic research area, which the interested reader can consult for additional details and viewpoints not included in our mini-review series (Hynes, 1994; Shattil et al., 1994; Parsons et al., 1994; Calvete, 1994; Schaller and ParMatrix Biology Vol. 16/1997, pp. 137-141 © 1997 by GustavFischerVerlag
sons, 1994; Clark and Brugge, 1995; Schwartz et al., 1995; Yamada and Miyamoto, 1995; Banes et al., 1995; Stewart et al., 1995; Huttenlocher et al., 1995; Edwards and Streuli, 1995; Bates et al., 1995; Rosales et al., 1995; Rozengurt, 1995; de Fougerolles et al., 1995; Lafrenie and Yamada, 1996; Gumbiner, 1996; Ruoslahti, 1996a,b; Juliano, 1996; Varner and Cheresh, 1996; Giancotti, 1996; Dedhar and Hannigan, 1996; Humphries, 1996; Guan and Chen, 1996; Newham and Humphries, 1996; Parsons, 1996; Sanchez-Mateos et al., 1996; LaFlamme and Auer, 1996; Sheppard, 1996; Lelievre et al., 1996; Tozer et al., 1996; Sjaastad and Nelson, 1997~ Hannigan and Dedhar, 1997; Newton et al., 1997; Wei et al., 1997; Parsons and Parsons, 1997; Hanks and Pohe, 1997; Kanazashi et al., 1997; Yamada and Geiger, 1997; Shattil and Ginsberg, 1997). Even though these reviews are superb, they often come from the established leadership in the field. For this mini-review series, we have deliberately sought out some
138
K.M. Yamada L
Reco~
TEGRIN Interactie
TM4
proteins lAP
Protease receptors Growth factor
~tside-ln " rgnaling
receptors caveolin
PLASMA MEMBRANE :~LASMIC DOMAINS
O
Calciuminflux ~ ~ OtherSignalingPathways Tyrosine / N phosphorylation ~ ~ ~ Growth,Apoptosis,Differentiation Multiplekinase Inositollipid activations pathways Organizationof the Cytoskeleton Figure 1. Schematic overview of integrin signaling, lntegrins provide functional links between ligands such as extracellular matrix molecules and the cytoplasm, using complex bi-directional signaling mechanisms and a host of intracellular pathways. See the text for discussion of this figure.
of the future leaders of the field who have not yet published an extensive series of reviews. Our goal was to highlight some of the freshest thinking in the field. An unusual additional feature of these mini-reviews was the explicit agreement with each reviewer to present at least one new generalization or novel testable hypothesis, to distinguish each mini-review from the current literature. The result is an intriguing, stimulating examination of the field as seen through new sets of eyes.
Overview of Integrin Signating Although the mini-reviews are each complete in themselves, it may help readers who are not members of the field to consider the following general aspects of the field of integrin signaling. One particularly intriguing general aspect of the development of this area has been finding that many of the specific pathways used by growth factors and oncogenes for signal transduction are also utilized by integrins. In addition, however, integrins have direct roles in the organization of the actincontaining cytoskeleton, which not only mediates changes in cell shape and movement, but which may
also contribute to the regulation of growth and differentiation by still-mysterious mechanisms. Moreover, novel signaling mechanisms are being discovered by the study of proteins that bind to integrin cytoplasmic domains and regulate integrin function. Figure 1 summarizes some of the key issues considered in this series. An early, crucial step in integrin signaling is recognition of the ligand by an integrin. The molecular basis of integrin recognition and binding of ligands is now understood at the level of specific key residues and binding domains in the ligand and the integrin receptor. As discussed in this series, the conformation and binding affinity of an integrin can be changed markedly by "inside-out" signaling, and novel insights into the nature of this process have come from studies of integrin-specific proteins that bind to a cytoplasmic domain and activate the integrin; in addition, cytoskeletal mechanisms of regulation have also been postulated. The process of ligand binding results in conformational changes in integrins, with alterations observed in the globular head region and in the beta subunit stalk domain, as detected by the appearance of new epitopes. Information associated with this conformational change is thought to be transmitted in some fashion across the
Integrin Signaling
139
PI3 Src
PK( -~ PL(
•~ CSI 0
~ Grb So.¢ m
SH~
p13 Crk PTI
Figure 2. Molecular interactions among components of cell adhesion and signaling complexes, lntegrin receptor occupancy and clustering by ligands results in the formation of large multi-molecular complexes of cytoskeletal and signaling proteins. Binding interactions known to occur between individual molecules are indicated by lines linking the proteins. Many other molecules, such as Rho, Rac, MAP kinases, and plectin, can also accumulate at least transiently in these integrin signaling and cytoskeletal complexes, but the nature of their intermolecular interactions remain to be clarified.
membrane, and one of our reviews proposes an intriguing new mechanism for this type of transduction. As indicated in some of the reviews, integrins can interact with a variety of other transmembrane molecules. An entirely new class of interactions with tetraspan (TM4) molecules has been discovered (e.g., see Berditchevski et al., 1996), which is likely to play significant roles in regulating or mediating integrin functions, lAP (integrin-associated protein) is another intriguing molecule associated with certain integrins (Lindberg et al., 1996). Even growth factor receptors can transiently associate with integrin-containing adhesion complexes and stimulate synergistic downstream signaling; the process is potentially byzantine, since growth factors often also alter the gene expression of integrins (e.g., see Schwartz et al., 1995; Cybulsky et al., 1994; Miyamoto et al., 1996; Kim and Yamada, 1997). Other interactions include the formation of complexes with protease receptors such as for urokinase, and a potential interaction with caveolin as reviewed in this series (see also Bohuslav et al., 1995 and Wary et al., 1996). Proceeding across the plasma membrane, the cytoplasmic domain or tail of each subunit is actually the only portion of each integrin that is directly "seen" by the cytoplasm. Several reviews in this series focus on these cy-
toplasmic tails, considering their molecular interactions and potential mechanisms for mediating signaling and even growth regulation. A staggering number of signaling events are triggered by integrins, and a partial list is provided in the lower portion of Figure 1. The reviews discuss many such important downstream events and propose intriguing new concepts. Besides signaling pathways, integrins have dramatic effects on the actin-containing cytoskeleton. Nevertheless, mechanistic understanding of integrin regulation of cytoskeletal organization is still in its infancy. Integrins bind to several cytoskeletal proteins including talin, cx-actinin, and tensin (e.g., see recent review by Yamada and Geiger, 1997). Additionally, however, integrin-induced adhesion complexes also include multifunctional docking molecules such as FAK (e.g. see the current mini-review by Guan, and previous reviews by Parsons et al., 1995; Hanks and Polte, 1997). The interactions within adhesion complexes involves both cytoskeletal and signaling molecules. As indicated in Figure 2, the binding interactions between these molecules appear remarkably complex and interconnected as they form three-dimensional molecular complexes such as the focal contact. The types and functional significance of some of these important interactions are explored in several of the reviews.
140
K . M . Yamada
This Mini-Renew Series This set of invited reviews provides a sampling of recent findings and concepts in a dynamic and rapidly growing field. It is obvious that mini-reviews and commentary from others would further enrich this research area. For example, there were several areas not covered by these mini-reviews. Examples include the dynamic organization of cytoplasmic proteins by integrins into large cytoskeletal and signaling complexes, as well as their cell surface mobility and roles in cell locomotion, which could serve as the topics of future mini-reviews. In addition, interactions of integrins with membrane-associated proteins such as a variety of T M 4 (tetraspan) proteins, protease receptors, and other integrin-associated proteins deserve detailed review. Because the authors of this particular series were for convenience only from the U.S., similarly creative reviews and c o m m e n tary from authors in Europe, Asia, and elsewhere would be valuable. Finally, even though this series deliberately focused on the thinking and new hypotheses from future leaders of the field, reviews and c o m m e n t a r y from the established leadership of the field would obviously also be welcome to p r o m o t e dialogue and to highlight additional exciting new paradigms.
References Banes, A.J., Tsuzaki, M., Yamamoto, J., Fischer, T., Brigman, B., Brown, T. and Miller, L.: Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals. Biochem. Cell Biol. 73: 349-365, 1995. Bates, R.C., Lincz, L.E and Burns, G.E: Involvement of integrins in cell survival. Cancer Metastasis Rev. 14: 191-203, 1995. Berditchevski, E, Zutter, M.M. and Hemler, M.E.: Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Mol. Biol. Cell 7- 193-207, 1996. Bohuslav, J., Horejsi, V., Hansmann, C., Stockl, J., Weidle, U.H., Majdic, O., Bartke, I., Knapp, W. and Stockinger, H.: Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. J. Exp. Med. 181: 1381-1390, 1995. Calvete, J.J.: Clues for understanding the structure and function of a prototypic human integrin: the platelet glycoprotein lib/Ilia complex. Thromb. Haemost. 72- 1-15, 1994. Clark, E.A. and Brugge, J.S.: Integrins and signal transduction pathways: the road taken. Science 268: 233-239, 1995. Cybulsky, A.V., McTavish, A.J. and Cyr, M.D.: Extracellular matrix modulates epidermal growth factor receptor activation in rat glomerular epithelial cells. J. Clin. Invest. 94" 68-78, 1994. de Fougerolles, A.R., Diamond, M.S. and Springer, T.A.: Heterogenous glycosylation of ICAM-3 and lack of interaction
with Mac-1 and p150,95. Eur. J. lmmunol. 25- 1008-1012, 1995. Dedhar, S. and Hannigan, G.E.: lntegrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr. Opin. Cell Biol. 8: 657-669, 1996. Edwards, G. and Streuli, C.: Signalling in extracellular-matrixmediated control of epithelial cell phenotype. Biochem. Soc. Trans. 23: 464--468, 1995. Giancotti, EG.: Signal transduction by the alpha 6 beta 4 integrin: charting the path between laminin binding and nuclear events. J. Cell Sci. 109:1165-1172, 1996. Guan, J i . and Chen, H.C.: Signal transduction in cell-matrix interactions. Int. Rev. Cytol. 168:81-121: 81-121, 1996. Gumbiner, B.M.: Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84: 345-357, 1996. Hanks, S.K. and Poke, T.R.: Signaling through focal adhesion kinase. Bioassays 19- 137-145, 1997. Hannigan, G.E. and Dedhar, S.: Protein kinase mediators of integrin signal transduction. J. Mol. Med. 75: 35-44, 1997. Humphries, M.J.: Integrin activation: the link between ligand binding and signal transduction. Curr. Opin. Cell Biol. 8: 632-640, 1996. Huttenlocher, A., Sandborg, R.R. and Horwitz, A.E: Adhesion in cell migration. Curr. Opin. Cell Biol. 7: 697-706, 1995. Hynes, R.O.: Genetic analyses of cell-matrix interactions in development. Curr. Opin. Genet. Dev. 4: 569-574, 1994. Juliano, R.: Cooperation between soluble factors and integrinmediated cell anchorage in the control of cell growth and differentiation. Bioassays 18- 911-917, 1996. Kanazashi, S.I., Sharma, C.P. and Arnaout, M.A.: Integrin-ligand interactions: scratching the surface. Curr. Opin. Hematol. 4: 67-74, 1997. Kim, L.T. and Yamada, K.M.: The regulation of expression of integrin receptors. Proc. Soc. Exp. Biol. Med. 214: 123-131, 1997. LaFlamme, S.E. and Auer, K.L.: Integrin signaling. Semin. CancerBiol. 7: 111-118, 1996. Lafrenie, R.M. and Yamada, K.M.: Integrin-dependent signal transduction. J. Cell Biochem. 61: 543-553, 1996. Lelievre, S., Weaver, V.M. and Bissell, M.J.: Extracellular matrix signaling from the cellular membrane skeleton to the nuclear skeleton: a model of gene regulation. Recent Prog. Horm. Res. 51:417-32: 417-432~ 1996. Lindberg, EP., Bullard, D.C., Caver, T.E., Gresham, H.D., Beaudet, A.L. and Brown, E.J.: Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274: 795-798, 1996. Miyamoto, S., Teramoto, H., Gutkind, J.S. and Yamada, K.M.: Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J. Cell Biol. 135: 1633-1642, 1996. Newham, P. and Humphries, M.J.: Integrin adhesion receptors: structure, function and implications for biomedicine. Mol. Med. Today 2: 304-313, 1996. Newton, R.A., Thiel, M. and Hogg, N.: Signaling mechanisms and the activation of leukocyte integrins. J. Leukoc. Biol. 61: 422-426, 1997. Parsons, J.T., Schaller, M.D., Hildebrand, J., Leu, T.H., Richardson, A. and Ote); C.: Focal adhesion kinase: structure and signalling. J. Cell Sci. Suppl. 18:109-13: 109-113, 1994. Parsons, J.T.: Integrin-mediated signaling - regulation by protein-tyrosine kinases and small GTP-binding proteins. Curr. Opin. Cell Biol. 8: 146-152, 1996.
Integrin Signaling Parsons, J.T. and Parsons, S.J.: Src family protein tyrosine kinases: cooperating with growth factor and adhesion signaling pathways. Curr. Opin. Cell Biol. 9: 187-192, 1997. Rosales, C., O'Brien, V., Kornberg, L. and Juliano, R.: Signal transduction by cell adhesion receptors. Biochim. Biophys. Acta 1242: 77-98, 1995. Rozengurt, E.- Convergent signalling in the action of integrins, neuropeptides, growth factors and oncogenes. Cancer Surv. 24: 81-96: 81-96, 1995. Ruoslahti, E.: RGD and other recognition sequences for integrins. Ann. Rev. Cell Dev. Biol. 12: 697-715, 1996a. Ruoslahti, E.: Integrin signaling and matrix assembly. Tumour Biol. 17: 117-124, 1996b. Sanchez-Mateos, P., Cabanas, C. and Sanchez-Madrid, E: Regulation of integrin function. Semin. Cancer Biol. 7: 99-109, 1996. Schaller, M.D. and Parsons, J.T.: Focal adhesion kinase and associated proteins. Curr. Opin. Cell Biol. 6: 705-710, 1994. Schwartz, M.A., Schaller, M.D. and Ginsberg, M.H.: Integrins emerging paradigms of signal-transduction. Annu. Rev. Cell DeL: Biol. 11: 549-599, 1995. Shattil, S.J., Ginsberg, M.H. and Brugge, J.S.: Adhesive signaling in platelets. Curr. Opin. Cell Biol. 6: 695-704, 1994. Shattil, S.J. and Ginsberg, M.H. (1997). Integrin signaling in vascular biology. J. Clin. Invest. (in press) Sheppard, D.: Epithelial integrins. Bioassays 18: 655-660, 1996. Sjaastad, M.D. and Nelson, W.J.: Integrin-mediated calcium signaling and regulation of cell adhesion by intracellular calcium. Bioassays 19: 47-55, 1997.
141
Stewart, M., Thiel, M. and Hogg, N.: Leukocyte integrins. Curr. Opin. Cell Biol. 7: 690-696, 1995. Tozer, E.C., Hughes, EE. and Loftus, J.C.: Ligand binding and affinity modulation of integrins. Biochem. Cell Biol. 74: 785-798, 1996. Varner, J.A. and Cheresh, D.A.: Integrins and cancer. Curr. Opin. Cell Biol. 8: 724-730, 1996. Wary, K.K., Mainiero, E, lsakoff, S.J., Marcantonio, E.E. and Giancotti, EG.: The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87: 733-743, 1996. Wei, J., Shaw, L.M. and Mercurio, A.M.: Integrin signaling in leukocytes: lessons from the alpha6betal integrin. J. Leukoc. Biol. 61: 397-407, 1997. Yamada, K.M. and Geiger, B.: Molecular interactions in cell adhesion complexes. Curr. Opin. Cell Biol. 9: 76-85, 1997. Yamada, K.M. and Miyamoto, S." Integrin transmembrane signaling and cytoskeletal control. Curr. Opin. Cell Biol. 7" 681-689, 1995.
-
Dr. Kenneth M. Yamada, Craniofacial Developmental Biology and Regeneration Branch, Building 30, Room 421, NIDR, NIH. 30 Convent Dr. MSC 4370 Bethesda, MD 20892-4370
Received July 2, 1997
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Integrin Signa[ing KENNETH M. YAMADA Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD, USA
Abstract Integrins provide dynamic links between cells and extracellular matrix molecules. Although integrins were originally viewed as relatively simple adhesion molecules, it soon became clear that intracellular signal transduction initiated by integrins is centrally involved in many cellular processes. In fact, a remarkable number of classical signaling pathways are now known to be activated or modified by the interactions of cells with matrix proteins via integrins. These integrin signaling responses can also involve many other extracellular and intracellular molecules. The following mini-reviews were solicited from some of the future leaders in the field of integrin signaling. They examine selected important portions of this field, provide conceptual syntheses from a large and confusing literature, and then propose novel testable ideas. These ideas should encourage dialogue and open new avenues of research in this rapidly expanding, exciting field. Key words: cell adhesion, cytoskeleton, extracellular matrix, integrin, signal transduction.
Introduction Integrins mediate both adhesion and bi-directional information transfer (Figure 1). Signaling information originating from binding interactions between integrins and extraceilular matrix molecules (ligands) is transduced across the plasma membrane into a variety of signal transduction pathways in a process termed "outsidein" signaling. In addition, however, intracellular regulators modify external integrin ligand-binding properties in a process termed "inside-out" signaling. There are many outstanding reviews in this field. A sampling from the >100 reviews on integrin signaling published in just the past couple of years include the following 3 dozen general reviews of various aspects of this dynamic research area, which the interested reader can consult for additional details and viewpoints not included in our mini-review series (Hynes, 1994; Shattil et al., 1994; Parsons et al., 1994; Calvete, 1994; Schaller and ParMatrix Biology Vol. 16/1997, pp. 137-141 © 1997 by GustavFischerVerlag
sons, 1994; Clark and Brugge, 1995; Schwartz et al., 1995; Yamada and Miyamoto, 1995; Banes et al., 1995; Stewart et al., 1995; Huttenlocher et al., 1995; Edwards and Streuli, 1995; Bates et al., 1995; Rosales et al., 1995; Rozengurt, 1995; de Fougerolles et al., 1995; Lafrenie and Yamada, 1996; Gumbiner, 1996; Ruoslahti, 1996a,b; Juliano, 1996; Varner and Cheresh, 1996; Giancotti, 1996; Dedhar and Hannigan, 1996; Humphries, 1996; Guan and Chen, 1996; Newham and Humphries, 1996; Parsons, 1996; Sanchez-Mateos et al., 1996; LaFlamme and Auer, 1996; Sheppard, 1996; Lelievre et al., 1996; Tozer et al., 1996; Sjaastad and Nelson, 1997~ Hannigan and Dedhar, 1997; Newton et al., 1997; Wei et al., 1997; Parsons and Parsons, 1997; Hanks and Pohe, 1997; Kanazashi et al., 1997; Yamada and Geiger, 1997; Shattil and Ginsberg, 1997). Even though these reviews are superb, they often come from the established leadership in the field. For this mini-review series, we have deliberately sought out some
138
K.M. Yamada L
Reco~
TEGRIN Interactie
TM4
proteins lAP
Protease receptors Growth factor
~tside-ln " rgnaling
receptors caveolin
PLASMA MEMBRANE :~LASMIC DOMAINS
O
Calciuminflux ~ ~ OtherSignalingPathways Tyrosine / N phosphorylation ~ ~ ~ Growth,Apoptosis,Differentiation Multiplekinase Inositollipid activations pathways Organizationof the Cytoskeleton Figure 1. Schematic overview of integrin signaling, lntegrins provide functional links between ligands such as extracellular matrix molecules and the cytoplasm, using complex bi-directional signaling mechanisms and a host of intracellular pathways. See the text for discussion of this figure.
of the future leaders of the field who have not yet published an extensive series of reviews. Our goal was to highlight some of the freshest thinking in the field. An unusual additional feature of these mini-reviews was the explicit agreement with each reviewer to present at least one new generalization or novel testable hypothesis, to distinguish each mini-review from the current literature. The result is an intriguing, stimulating examination of the field as seen through new sets of eyes.
Overview of Integrin Signating Although the mini-reviews are each complete in themselves, it may help readers who are not members of the field to consider the following general aspects of the field of integrin signaling. One particularly intriguing general aspect of the development of this area has been finding that many of the specific pathways used by growth factors and oncogenes for signal transduction are also utilized by integrins. In addition, however, integrins have direct roles in the organization of the actincontaining cytoskeleton, which not only mediates changes in cell shape and movement, but which may
also contribute to the regulation of growth and differentiation by still-mysterious mechanisms. Moreover, novel signaling mechanisms are being discovered by the study of proteins that bind to integrin cytoplasmic domains and regulate integrin function. Figure 1 summarizes some of the key issues considered in this series. An early, crucial step in integrin signaling is recognition of the ligand by an integrin. The molecular basis of integrin recognition and binding of ligands is now understood at the level of specific key residues and binding domains in the ligand and the integrin receptor. As discussed in this series, the conformation and binding affinity of an integrin can be changed markedly by "inside-out" signaling, and novel insights into the nature of this process have come from studies of integrin-specific proteins that bind to a cytoplasmic domain and activate the integrin; in addition, cytoskeletal mechanisms of regulation have also been postulated. The process of ligand binding results in conformational changes in integrins, with alterations observed in the globular head region and in the beta subunit stalk domain, as detected by the appearance of new epitopes. Information associated with this conformational change is thought to be transmitted in some fashion across the
Integrin Signaling
139
PI3 Src
PK( -~ PL(
•~ CSI 0
~ Grb So.¢ m
SH~
p13 Crk PTI
Figure 2. Molecular interactions among components of cell adhesion and signaling complexes, lntegrin receptor occupancy and clustering by ligands results in the formation of large multi-molecular complexes of cytoskeletal and signaling proteins. Binding interactions known to occur between individual molecules are indicated by lines linking the proteins. Many other molecules, such as Rho, Rac, MAP kinases, and plectin, can also accumulate at least transiently in these integrin signaling and cytoskeletal complexes, but the nature of their intermolecular interactions remain to be clarified.
membrane, and one of our reviews proposes an intriguing new mechanism for this type of transduction. As indicated in some of the reviews, integrins can interact with a variety of other transmembrane molecules. An entirely new class of interactions with tetraspan (TM4) molecules has been discovered (e.g., see Berditchevski et al., 1996), which is likely to play significant roles in regulating or mediating integrin functions, lAP (integrin-associated protein) is another intriguing molecule associated with certain integrins (Lindberg et al., 1996). Even growth factor receptors can transiently associate with integrin-containing adhesion complexes and stimulate synergistic downstream signaling; the process is potentially byzantine, since growth factors often also alter the gene expression of integrins (e.g., see Schwartz et al., 1995; Cybulsky et al., 1994; Miyamoto et al., 1996; Kim and Yamada, 1997). Other interactions include the formation of complexes with protease receptors such as for urokinase, and a potential interaction with caveolin as reviewed in this series (see also Bohuslav et al., 1995 and Wary et al., 1996). Proceeding across the plasma membrane, the cytoplasmic domain or tail of each subunit is actually the only portion of each integrin that is directly "seen" by the cytoplasm. Several reviews in this series focus on these cy-
toplasmic tails, considering their molecular interactions and potential mechanisms for mediating signaling and even growth regulation. A staggering number of signaling events are triggered by integrins, and a partial list is provided in the lower portion of Figure 1. The reviews discuss many such important downstream events and propose intriguing new concepts. Besides signaling pathways, integrins have dramatic effects on the actin-containing cytoskeleton. Nevertheless, mechanistic understanding of integrin regulation of cytoskeletal organization is still in its infancy. Integrins bind to several cytoskeletal proteins including talin, cx-actinin, and tensin (e.g., see recent review by Yamada and Geiger, 1997). Additionally, however, integrin-induced adhesion complexes also include multifunctional docking molecules such as FAK (e.g. see the current mini-review by Guan, and previous reviews by Parsons et al., 1995; Hanks and Polte, 1997). The interactions within adhesion complexes involves both cytoskeletal and signaling molecules. As indicated in Figure 2, the binding interactions between these molecules appear remarkably complex and interconnected as they form three-dimensional molecular complexes such as the focal contact. The types and functional significance of some of these important interactions are explored in several of the reviews.
140
K . M . Yamada
This Mini-Renew Series This set of invited reviews provides a sampling of recent findings and concepts in a dynamic and rapidly growing field. It is obvious that mini-reviews and commentary from others would further enrich this research area. For example, there were several areas not covered by these mini-reviews. Examples include the dynamic organization of cytoplasmic proteins by integrins into large cytoskeletal and signaling complexes, as well as their cell surface mobility and roles in cell locomotion, which could serve as the topics of future mini-reviews. In addition, interactions of integrins with membrane-associated proteins such as a variety of T M 4 (tetraspan) proteins, protease receptors, and other integrin-associated proteins deserve detailed review. Because the authors of this particular series were for convenience only from the U.S., similarly creative reviews and c o m m e n tary from authors in Europe, Asia, and elsewhere would be valuable. Finally, even though this series deliberately focused on the thinking and new hypotheses from future leaders of the field, reviews and c o m m e n t a r y from the established leadership of the field would obviously also be welcome to p r o m o t e dialogue and to highlight additional exciting new paradigms.
References Banes, A.J., Tsuzaki, M., Yamamoto, J., Fischer, T., Brigman, B., Brown, T. and Miller, L.: Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals. Biochem. Cell Biol. 73: 349-365, 1995. Bates, R.C., Lincz, L.E and Burns, G.E: Involvement of integrins in cell survival. Cancer Metastasis Rev. 14: 191-203, 1995. Berditchevski, E, Zutter, M.M. and Hemler, M.E.: Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Mol. Biol. Cell 7- 193-207, 1996. Bohuslav, J., Horejsi, V., Hansmann, C., Stockl, J., Weidle, U.H., Majdic, O., Bartke, I., Knapp, W. and Stockinger, H.: Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. J. Exp. Med. 181: 1381-1390, 1995. Calvete, J.J.: Clues for understanding the structure and function of a prototypic human integrin: the platelet glycoprotein lib/Ilia complex. Thromb. Haemost. 72- 1-15, 1994. Clark, E.A. and Brugge, J.S.: Integrins and signal transduction pathways: the road taken. Science 268: 233-239, 1995. Cybulsky, A.V., McTavish, A.J. and Cyr, M.D.: Extracellular matrix modulates epidermal growth factor receptor activation in rat glomerular epithelial cells. J. Clin. Invest. 94" 68-78, 1994. de Fougerolles, A.R., Diamond, M.S. and Springer, T.A.: Heterogenous glycosylation of ICAM-3 and lack of interaction
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Dr. Kenneth M. Yamada, Craniofacial Developmental Biology and Regeneration Branch, Building 30, Room 421, NIDR, NIH. 30 Convent Dr. MSC 4370 Bethesda, MD 20892-4370
Received July 2, 1997