JOURNAL OFPATHOLOGY, VOL.
161: 189-190 (1990)
EDITORIAL CELLULAR FUNCTIONS OF ADHESION MOLECULES There have been considerable advances in our understanding of the molecular basis of cell adhesion and its contribution to various cellular processes in the two decades since Curtis’s review.’ The normal function of cell adhesion molecules (CAM) and substratum adhesion molecules (SAM) are clearly important in the maintenance of tissue integrity, but the same molecules are also involved in other functions. The major cell adhesion moleculeshave been analysed by functional and structural criteria and have been shown to belong to at least three distinct families. The cadherin family exhibit calcium dependent homophilic binding and includes the main adhesion molecules of the adhesive cell junctions, L-CAM or A-CAM in adherens junctions and desmosomal glycoprotein 1 in desmosomes.* The cell adhesive property of these molecules involves trans binding of cadherins on different cells, and the assembly of junctions is achieved by cis binding of these molecules on the same cell surface and the interaction of the cytoplasmic domains with junctional plaque components. A second group of CAMs belong to a subset of the immunoglobulin gene superfamily and includes N-CAM, ICAM-1 and CEA.3 These molecules function by calcium independent binding, which may be either homophilic (N-CAM) or heterophilic (ICAM- 1). The third important group of adhesion molecules are the integrin receptors: These are heterodimeric transmembrane glycoproteins which bind to ligands containing the tripeptide sequence arg-gly-asp (RGD). The ligand binding is a property of the a chain, which is specific for the different integrin receptors, but linkage to the cytoskeleton is a property of the chain which may be common to several of these receptors. The expression and functional activity of CAMs are regulators of cell differentiation. The early stage of the mesenchymakpithelial transformation during renal development involves these molecules. Laminin, fibronectin and type IV collagen are secreted in a polarized distribution, and the developing epithelial cells adhere to these by integrin receptors. Further differentiation of the epithelium 0022-341 7,/90/070189-02$05.00 0 1990 by John Wiley & Sons, Ltd.
and maintenance of the epithelial phenotype requires intercellular adhesion mediated by cadherins.’*6 Loss of this intercellular adhesion during neoplastic transformation may be accompanied by reversal of epithelial differentiation. A similar contribution of all three CAM families has been shown during embryonic development of other tissues. Transfection of L-cells by cDNA for cadherins results not only in enhanced intercellular adhesion but also rofound phenotypic changes in the adhering cells. Some of the intercellular co-operation important in focusing inflammatory and immune responses involve CAMs. The antigen independent stage of interaction between T lymphocytes and some accessory cells depends on the molecular interaction of ICAM-1 and LFA-1.9 ICAM-1 (CD54) expressed by these cells is a member of the immunoglobulin gene superfamily, part of which is recognized as a ligand by LFA-1, an integrin receptor on T cells. Recent work has shown that adhesion of lymphocytes to endothelium in inflammatory tissues also depends on interaction of an integrin receptor on lymphocytes (VLA) and an interferon inducible CAM of the immunoglobulin gene superfamily V-CAM 1 expressed by endothelium.” V-CAM1 and its gene were isolated by the novel method of screening endothlial cDNA clones expressed in a eukaryotic system by the adhesion of lymphocytes. Integrin receptors are involved in several cellular processes of phagocytic cells. During cell death by apoptosis there is a cell surface mechanism by which macrophages recognize and phagocytose the senescent cell, but do not become activated. It has now been shown that vitronectin receptors on the macrophages mediate this by an RGD dependent recognition of the apoptotic cell.” Some leukocyte cell surface receptors for the C, fragment of complement are also members of the integrin family and may be involved in antibody and complement dependent phagocytosis.’* Some CAMSexhibit interaction with the cytoskeleton and may act as substrates during cell activation
r
I 90
EDITORIAL
dependent tyrosine kinase activity.The phosphorylREFERENCES ated tyrosine on the integnn of transformed avian I. Curtis ASG. The Cell Surface: Its Molecular Role in Morphogenesis. cells lies in a region of the cytoplasmicdomain which New York: Academic Press, 1967. shows homology with part of the EGF re~eptor.’~ 2. Takaichi M. The cadherins: Cell-all adhesion molecules controlling animal morphogcncsis. Development 1988; 102: 6 3 M 5 5 . This region is also involved in the transmembrane Williams AF, Barclay AN. The immunoglobulin supcrfamilydolinkage of cell substratum adhesion with actin 3. mains for a l l surfaa recognition.Ann Rev fmmunoll988 6 381-406. filaments. 4. H y n s RO. Integrins: A family o f a l l surface receptors. Cell 1987; 48: 549-554. Finally, loss of cell adhesion may result in disease 5. Ekblom P, Theslcff I. Role of transfemn and extracellular matrix states. Several inherited disorders of integrin recepcomponents in kidney differentiation. Mol Cell Biol 1985; 4: 85-97. tor function have been described. In Glanzmann’s 6. Garrod DR, Fleming S.Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos. thrombasthenia, defective platelet adhesion to exDevelopmenl 1990; 10%:313-322. tracellular proteins occurs because of loss of the 7. Edelman GM. Morphoregulatory molecules. Biochemistry 1988; 27: 3533-3543. integrin molecule glycoprotein 11b/l 1la.4ImmunoMage R-M, Matsuzaki F, Gallin WS, Goldberg JI, Cunningham BA. deficiency syndromes have been described in which 8. Edelman GM. Construction of epiothelioid sheets by transfection of the primary defect is loss of the LFA-l/ICAM-1 mouse sarcoma cells with cDNAs for chick a l l adhesion molecules. Proc Not1 AcadSci USA 1988; 85: 7272-7278. interaction between antigen presenting cells and T 9. Simmers D, Makgoba MW, Seed B. ICAM, an adhesion ligand of lymphocytes.I2Acquired loss ofcell adhesion is seen LFA-I, is homologous to the neural cell adhesion molecule NCAM. Name 1988; 331: 624.627. in the immunologically mediated bullous diseases. L, Hessian C,Tizard R, ei a/. Direct expression cloning of Stanley’s group have shown that the target antigen 10. Osbom vascular cell adhesion molecule 1, a cytokine-induced endothelial of autoantibodies in pemphigus foliaceus is the protein that binds to lymphocytes. Cell 1989; 59: 120>121 I . desmosomal glycoprotein 1-plakoglobin complex, 1 1 . Savill J, Dransfield 1, Hogg N, Haslett C. Vitronectin reaptormediated phagocytosis of cells undergoing apoptosis. Nature 1990; although the precise mechanism of acantholysis re30:170-173. mains to be defined.I4 Finally, some genetic alter- 12. Springer TA. The LFA-I, Mac-I glycoprotein family and its deficiencyin an inherited disease. FedProc 1985; 42-2663. ations associated with tumour progression appear to 13. Tamkun JW, l3c Simone DW, Fonda D, et a/.Structure of integrin, a be associated with loss of genetic material encodlng glycoprotcin inrolvcd in the transmembrane linkage between fibrocell adhesion molecules. ncctin and actin. Cell 1986; &.271-282. E m RW, Stanley J. Identification of pemphigus vulgaris antigen Cell adhesion molecules show evolutionary con- 14. extracted from normal human epidermis and comparison with pemservation” and are now known to be involved in phigus foliaaus antigen. J Clin Invest 1977;81: 807-812. many aspects of cell biology of importance to path- 15. Brower DL, Jaffe SM. Requirement for integrins during Drosophila wing development. Nature 1989; 342:285-287. ologists. Research on the molecular basis of their function and its control will add to our understanding of many different aspects of disease.
STEWART FLEMING Department of Pathology University of Edinburgh Edinburgh EH8 9AG, U.K.
161: 189-190 (1990)
EDITORIAL CELLULAR FUNCTIONS OF ADHESION MOLECULES There have been considerable advances in our understanding of the molecular basis of cell adhesion and its contribution to various cellular processes in the two decades since Curtis’s review.’ The normal function of cell adhesion molecules (CAM) and substratum adhesion molecules (SAM) are clearly important in the maintenance of tissue integrity, but the same molecules are also involved in other functions. The major cell adhesion moleculeshave been analysed by functional and structural criteria and have been shown to belong to at least three distinct families. The cadherin family exhibit calcium dependent homophilic binding and includes the main adhesion molecules of the adhesive cell junctions, L-CAM or A-CAM in adherens junctions and desmosomal glycoprotein 1 in desmosomes.* The cell adhesive property of these molecules involves trans binding of cadherins on different cells, and the assembly of junctions is achieved by cis binding of these molecules on the same cell surface and the interaction of the cytoplasmic domains with junctional plaque components. A second group of CAMs belong to a subset of the immunoglobulin gene superfamily and includes N-CAM, ICAM-1 and CEA.3 These molecules function by calcium independent binding, which may be either homophilic (N-CAM) or heterophilic (ICAM- 1). The third important group of adhesion molecules are the integrin receptors: These are heterodimeric transmembrane glycoproteins which bind to ligands containing the tripeptide sequence arg-gly-asp (RGD). The ligand binding is a property of the a chain, which is specific for the different integrin receptors, but linkage to the cytoskeleton is a property of the chain which may be common to several of these receptors. The expression and functional activity of CAMs are regulators of cell differentiation. The early stage of the mesenchymakpithelial transformation during renal development involves these molecules. Laminin, fibronectin and type IV collagen are secreted in a polarized distribution, and the developing epithelial cells adhere to these by integrin receptors. Further differentiation of the epithelium 0022-341 7,/90/070189-02$05.00 0 1990 by John Wiley & Sons, Ltd.
and maintenance of the epithelial phenotype requires intercellular adhesion mediated by cadherins.’*6 Loss of this intercellular adhesion during neoplastic transformation may be accompanied by reversal of epithelial differentiation. A similar contribution of all three CAM families has been shown during embryonic development of other tissues. Transfection of L-cells by cDNA for cadherins results not only in enhanced intercellular adhesion but also rofound phenotypic changes in the adhering cells. Some of the intercellular co-operation important in focusing inflammatory and immune responses involve CAMs. The antigen independent stage of interaction between T lymphocytes and some accessory cells depends on the molecular interaction of ICAM-1 and LFA-1.9 ICAM-1 (CD54) expressed by these cells is a member of the immunoglobulin gene superfamily, part of which is recognized as a ligand by LFA-1, an integrin receptor on T cells. Recent work has shown that adhesion of lymphocytes to endothelium in inflammatory tissues also depends on interaction of an integrin receptor on lymphocytes (VLA) and an interferon inducible CAM of the immunoglobulin gene superfamily V-CAM 1 expressed by endothelium.” V-CAM1 and its gene were isolated by the novel method of screening endothlial cDNA clones expressed in a eukaryotic system by the adhesion of lymphocytes. Integrin receptors are involved in several cellular processes of phagocytic cells. During cell death by apoptosis there is a cell surface mechanism by which macrophages recognize and phagocytose the senescent cell, but do not become activated. It has now been shown that vitronectin receptors on the macrophages mediate this by an RGD dependent recognition of the apoptotic cell.” Some leukocyte cell surface receptors for the C, fragment of complement are also members of the integrin family and may be involved in antibody and complement dependent phagocytosis.’* Some CAMSexhibit interaction with the cytoskeleton and may act as substrates during cell activation
r
I 90
EDITORIAL
dependent tyrosine kinase activity.The phosphorylREFERENCES ated tyrosine on the integnn of transformed avian I. Curtis ASG. The Cell Surface: Its Molecular Role in Morphogenesis. cells lies in a region of the cytoplasmicdomain which New York: Academic Press, 1967. shows homology with part of the EGF re~eptor.’~ 2. Takaichi M. The cadherins: Cell-all adhesion molecules controlling animal morphogcncsis. Development 1988; 102: 6 3 M 5 5 . This region is also involved in the transmembrane Williams AF, Barclay AN. The immunoglobulin supcrfamilydolinkage of cell substratum adhesion with actin 3. mains for a l l surfaa recognition.Ann Rev fmmunoll988 6 381-406. filaments. 4. H y n s RO. Integrins: A family o f a l l surface receptors. Cell 1987; 48: 549-554. Finally, loss of cell adhesion may result in disease 5. Ekblom P, Theslcff I. Role of transfemn and extracellular matrix states. Several inherited disorders of integrin recepcomponents in kidney differentiation. Mol Cell Biol 1985; 4: 85-97. tor function have been described. In Glanzmann’s 6. Garrod DR, Fleming S.Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos. thrombasthenia, defective platelet adhesion to exDevelopmenl 1990; 10%:313-322. tracellular proteins occurs because of loss of the 7. Edelman GM. Morphoregulatory molecules. Biochemistry 1988; 27: 3533-3543. integrin molecule glycoprotein 11b/l 1la.4ImmunoMage R-M, Matsuzaki F, Gallin WS, Goldberg JI, Cunningham BA. deficiency syndromes have been described in which 8. Edelman GM. Construction of epiothelioid sheets by transfection of the primary defect is loss of the LFA-l/ICAM-1 mouse sarcoma cells with cDNAs for chick a l l adhesion molecules. Proc Not1 AcadSci USA 1988; 85: 7272-7278. interaction between antigen presenting cells and T 9. Simmers D, Makgoba MW, Seed B. ICAM, an adhesion ligand of lymphocytes.I2Acquired loss ofcell adhesion is seen LFA-I, is homologous to the neural cell adhesion molecule NCAM. Name 1988; 331: 624.627. in the immunologically mediated bullous diseases. L, Hessian C,Tizard R, ei a/. Direct expression cloning of Stanley’s group have shown that the target antigen 10. Osbom vascular cell adhesion molecule 1, a cytokine-induced endothelial of autoantibodies in pemphigus foliaceus is the protein that binds to lymphocytes. Cell 1989; 59: 120>121 I . desmosomal glycoprotein 1-plakoglobin complex, 1 1 . Savill J, Dransfield 1, Hogg N, Haslett C. Vitronectin reaptormediated phagocytosis of cells undergoing apoptosis. Nature 1990; although the precise mechanism of acantholysis re30:170-173. mains to be defined.I4 Finally, some genetic alter- 12. Springer TA. The LFA-I, Mac-I glycoprotein family and its deficiencyin an inherited disease. FedProc 1985; 42-2663. ations associated with tumour progression appear to 13. Tamkun JW, l3c Simone DW, Fonda D, et a/.Structure of integrin, a be associated with loss of genetic material encodlng glycoprotcin inrolvcd in the transmembrane linkage between fibrocell adhesion molecules. ncctin and actin. Cell 1986; &.271-282. E m RW, Stanley J. Identification of pemphigus vulgaris antigen Cell adhesion molecules show evolutionary con- 14. extracted from normal human epidermis and comparison with pemservation” and are now known to be involved in phigus foliaaus antigen. J Clin Invest 1977;81: 807-812. many aspects of cell biology of importance to path- 15. Brower DL, Jaffe SM. Requirement for integrins during Drosophila wing development. Nature 1989; 342:285-287. ologists. Research on the molecular basis of their function and its control will add to our understanding of many different aspects of disease.
STEWART FLEMING Department of Pathology University of Edinburgh Edinburgh EH8 9AG, U.K.
