CD44 Function
Published by Anonymous on 2007/9/30 (2403 reads)
1: Results Probl Cell Differ. 2001;33:85-103.
Structure and function of CD44: characteristic molecular features and analysis of the hyaluronan binding site.
Bajorath J.
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Publication Types:
Review
PMID: 11190680 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Adv Cancer Res. 2000;77:169-87.
CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value.
Wielenga VJ, van der Neut R, Offerhaus GJ, Pals ST.
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 10549358 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Mol Pathol. 1998 Aug;51(4):191-200.
The normal structure and function of CD44 and its role in neoplasia.
Sneath RJ, Mangham DC.
Royal Orthopaedic Hospital Oncology Service, Birmingham, UK.
CD44 is a transmembrane glycoprotein, the variant isoforms of which are coded for by alternative splicing, with the most prolific isoform being CD44 standard. CD44 is found in a wide variety of tissues including the central nervous system, lung, epidermis, liver, and pancreas, whereas variant isoforms of CD44 (CD44v) appear to have a much more restricted distribution. Variants of CD44 are expressed in tissues during development, including embryonic epithelia. Known functions of CD44 are cellular adhesion (aggregation and migration), hyaluronate degradation, lymphocyte activation, lymph node homing, myelopoiesis and lymphopoiesis, angiogenesis, and release of cytokines. The functions of CD44 are principally dependant on cellular adhesion in one setting or another. The role of CD44 in neoplasia is less well defined, although metastatic potential can be conferred on non-metastasising cell lines by transfection with a variant of CD44 and high levels of CD44 are associated with several types of malignant tumours. The physiological functions of CD44 indicate that the molecule could be involved in the metastatic spread of tumours. Many studies have investigated the pattern of CD44 distribution in tumours and some observations suggest that certain cells do not use CD44 in tumorigenesis or in the production of metastases. However, the data are extremely conflicting, and further studies are needed to establish the prognostic value of CD44 and its variant isoforms. The precise function of CD44 in the metastatic process and the degree of involvement in human malignancies has yet to be established fully.
Publication Types:
Review
PMID: 9893744 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Cell Adhes Commun. 1998;6(2-3):157-60.
CD44 variant isoforms are essential for the function of epidermal Langerhans cells and dendritic cells.
Weiss JM, Renkl AC, Sleeman J, Dittmar H, Termeer CC, Taxis S, Howells N, Schöpf E, Ponta H, Herrlich P, Simon JC.
Department of Dermatology, University of Freiburg, Germany. Weiss@haul.ukl.uni-freiburg.de
Upon antigen encounter epidermal Langerhans cells (LC) and dendritic cells (DC) emigrate from peripheral organs and invade lymph nodes through the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Part of this process is mimicked by metastasizing tumor cells. Since splice variants of CD44 promote metastasis to lymph nodes we explored the expression of CD44 proteins on migrating LC and DC. We show that following antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6 and v9. Antibodies against CD44 epitopes arrest LC in the epidermis, prevent the binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9823467 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Front Biosci. 1998 Jul 1;3:d616-30.
CD44 structure and function.
Lesley J, Hyman R.
Cancer Biology Laboratory, The Salk Institute for Biological Studies, P.O. Box 85800, San Diego CA 92186-5800, USA. lesley@dcbsun.salk.edu
In this review we discuss the structural elements of CD44 that have been shown to be involved in specific functions. To this end, we focus primarily on experiments in which CD44 constructs are transfected into cells whose function is then assayed. The hyaluronan binding function of CD44 has been assayed in cell lines and in fusion proteins, termed CD44-Igs, consisting of the external domain of CD44 coupled to the hinge, CH2 and CH3 regions of human IgG1. These studies have shown that hyaluronan binding by CD44 is regulated by the cells in which it is expressed, and that at least part of this regulation is determined by cell specific posttranslational modifications, especially N-glycosylation, of CD44 itself. Variant isoforms of CD44 determined by alternative splicing of 11 optional exons in the middle of the gene determine additional functions of CD44, as well as contributing to the regulation of hyaluronan binding. Soluble CD44 may modulate the function of cell surface CD44. The cytoplasmic domain of CD44 contributes to ligand binding in a way that remains obscure. It also determines membrane localization in polarized epithelial cells, and is probably involved in CD44 interactions with the cytoskeleton and in mediating post-ligand binding events.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9634544 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Curr Opin Cell Biol. 1997 Oct;9(5):635-42.
The importance of cellular environment to function of the CD44 matrix receptor.
Kincade PW, Zheng Z, Katoh S, Hanson L.
Oklahoma Medical Research Foundation, Oklahoma City 73104, USA. paul-kincade@omrf.ouhsc.edu
Much has been learned recently by experimental manipulation of the structure of CD44 and assessment of the resulting functions. However, even greater structural variation is naturally introduced by CD44-bearing cells. A structural model is now available for the portion of CD44 that recognizes hyaluronan, but it is clear that all domains of the molecule influence CD44 functions.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9330866 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Adv Cancer Res. 1997;71:241-319.
CD44: structure, function, and association with the malignant process.
Naor D, Sionov RV, Ish-Shalom D.
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
CD44 is a ubiquitous multistructural and multifunctional cells surface adhesion molecule involved in cell-cell and cell-matrix interactions. Twenty exons are involved in the genomic organization of this molecule. The first five and the last 5 exons are constant, whereas the 10 exons located between these regions are subjected to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons, as well as variations in N-glycosylation, O-glycosylation, and glycosaminoglycanation (by heparan sulfate or chondroitin sulfate), generate multiple isoforms (at least 20 are known) of different molecular sizes (85-230 kDa). The smallest CD44 molecule (85-95 kDa), which lacks the entire variable region, is standard CD44 (CD44s). As it is expressed mainly on cells of lymphohematopoietic origin, CD44s is also known as hematopoietic CD44 (CD44H). CD44s is a single-chain molecule composed of a distal extracellular domain (containing, the ligand-binding sites), a membrane-proximal region, a transmembrane-spanning domain, and a cytoplasmic tail. The molecular sequence (with the exception of the membrane-proximal region) displays high interspecies homology. After immunological activation, T lymphocytes and other leukocytes transiently upregulate CD44 isoforms expressing variant exons (designated CD44v). A CD44 isform containing the last 3 exon products of the variable region (CD44V8-10, also known as epithelial CD44 or CD44E), is preferentially expressed on epithelial cells. The longest CD44 isoform expressing in tandem eight exons of the variable region (CD44V3-10) was detected in keratinocytes. Hyaluronic acid (HA), an important component of the extracellular matrix (ECM), is the principal, but by no means the only, ligand of CD44. Other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate. Mucosal addressin, serglycin, osteopontin, and the class II invariant chain (Ii) are additional, ECM-unrelated, ligands of the molecule. In many, but not in all cases, CD44 does not bind HA unless it is stimulated by phorbol esters, activated by agonistic anti-CD44 antibody, or deglycosylated (e.g., by tunicamycin). CD44 is a multifunctional receptor involved in cell-cell and cell-ECM interactions, cell traffic, lymph node homing, presentation of chemokines and growth factors to traveling cells, and transmission of growth signals. CD44 also participates in the uptake and intracellular degradation of HA, as well as in transmission of signals mediating hematopoiesis and apoptosis. Many cancer cell types as well as their metastases express high levels of CD44. Whereas some tumors, such as gliomas, exclusively express standard CD44, other neoplasms, including gastrointestinal cancer, bladder cancer, uterine cervical cancer, breast cancer and non-Hodgkin's lymphomas, also express CD44 variants. Hence CD44, particularly its variants, may be used as diagnostic or prognostic markers of at least some human malignant diseases. Furthermore, it has been shown in animal models that injection of reagents interfering with CD44-ligand interaction (e.g., CD44s- or CD44v-specific antibodies) inhibit local tumor growth and metastatic spread. These findings suggest that CD44 may confer a growth advantage on some neoplastic cells and, therefore, could be used as a target for cancer therapy. It is hoped that identification of CD44 variants expressed on cancer but not on normal cells will lead to the development of anti-CD44 reagents restricted to the neoplastic growth.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9111868 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pol Arch Med Wewn. 1996 Sep;96(3):297-302.
[CD44--cell receptor for hyaluronate. Clinical aspects of structure and function]
[Article in Polish]
Matysiak W.
Zakładu Immunologii Klinicznej Akademii Medycznej, Lublinie.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9122023 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: J Cell Sci. 1994 Sep;107 ( Pt 9):2353-9.
The role of the cytoplasmic domain in regulating CD44 function.
Isacke CM.
Department of Biology, Imperial College of Science, Technology and Medicine, London, UK.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7531197 [PubMed - indexed for MEDLINE]
Structure and function of CD44: characteristic molecular features and analysis of the hyaluronan binding site.
Bajorath J.
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Publication Types:
Review
PMID: 11190680 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Adv Cancer Res. 2000;77:169-87.
CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value.
Wielenga VJ, van der Neut R, Offerhaus GJ, Pals ST.
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 10549358 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Mol Pathol. 1998 Aug;51(4):191-200.
The normal structure and function of CD44 and its role in neoplasia.
Sneath RJ, Mangham DC.
Royal Orthopaedic Hospital Oncology Service, Birmingham, UK.
CD44 is a transmembrane glycoprotein, the variant isoforms of which are coded for by alternative splicing, with the most prolific isoform being CD44 standard. CD44 is found in a wide variety of tissues including the central nervous system, lung, epidermis, liver, and pancreas, whereas variant isoforms of CD44 (CD44v) appear to have a much more restricted distribution. Variants of CD44 are expressed in tissues during development, including embryonic epithelia. Known functions of CD44 are cellular adhesion (aggregation and migration), hyaluronate degradation, lymphocyte activation, lymph node homing, myelopoiesis and lymphopoiesis, angiogenesis, and release of cytokines. The functions of CD44 are principally dependant on cellular adhesion in one setting or another. The role of CD44 in neoplasia is less well defined, although metastatic potential can be conferred on non-metastasising cell lines by transfection with a variant of CD44 and high levels of CD44 are associated with several types of malignant tumours. The physiological functions of CD44 indicate that the molecule could be involved in the metastatic spread of tumours. Many studies have investigated the pattern of CD44 distribution in tumours and some observations suggest that certain cells do not use CD44 in tumorigenesis or in the production of metastases. However, the data are extremely conflicting, and further studies are needed to establish the prognostic value of CD44 and its variant isoforms. The precise function of CD44 in the metastatic process and the degree of involvement in human malignancies has yet to be established fully.
Publication Types:
Review
PMID: 9893744 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Cell Adhes Commun. 1998;6(2-3):157-60.
CD44 variant isoforms are essential for the function of epidermal Langerhans cells and dendritic cells.
Weiss JM, Renkl AC, Sleeman J, Dittmar H, Termeer CC, Taxis S, Howells N, Schöpf E, Ponta H, Herrlich P, Simon JC.
Department of Dermatology, University of Freiburg, Germany. Weiss@haul.ukl.uni-freiburg.de
Upon antigen encounter epidermal Langerhans cells (LC) and dendritic cells (DC) emigrate from peripheral organs and invade lymph nodes through the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Part of this process is mimicked by metastasizing tumor cells. Since splice variants of CD44 promote metastasis to lymph nodes we explored the expression of CD44 proteins on migrating LC and DC. We show that following antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6 and v9. Antibodies against CD44 epitopes arrest LC in the epidermis, prevent the binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9823467 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Front Biosci. 1998 Jul 1;3:d616-30.
CD44 structure and function.
Lesley J, Hyman R.
Cancer Biology Laboratory, The Salk Institute for Biological Studies, P.O. Box 85800, San Diego CA 92186-5800, USA. lesley@dcbsun.salk.edu
In this review we discuss the structural elements of CD44 that have been shown to be involved in specific functions. To this end, we focus primarily on experiments in which CD44 constructs are transfected into cells whose function is then assayed. The hyaluronan binding function of CD44 has been assayed in cell lines and in fusion proteins, termed CD44-Igs, consisting of the external domain of CD44 coupled to the hinge, CH2 and CH3 regions of human IgG1. These studies have shown that hyaluronan binding by CD44 is regulated by the cells in which it is expressed, and that at least part of this regulation is determined by cell specific posttranslational modifications, especially N-glycosylation, of CD44 itself. Variant isoforms of CD44 determined by alternative splicing of 11 optional exons in the middle of the gene determine additional functions of CD44, as well as contributing to the regulation of hyaluronan binding. Soluble CD44 may modulate the function of cell surface CD44. The cytoplasmic domain of CD44 contributes to ligand binding in a way that remains obscure. It also determines membrane localization in polarized epithelial cells, and is probably involved in CD44 interactions with the cytoskeleton and in mediating post-ligand binding events.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9634544 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Curr Opin Cell Biol. 1997 Oct;9(5):635-42.
The importance of cellular environment to function of the CD44 matrix receptor.
Kincade PW, Zheng Z, Katoh S, Hanson L.
Oklahoma Medical Research Foundation, Oklahoma City 73104, USA. paul-kincade@omrf.ouhsc.edu
Much has been learned recently by experimental manipulation of the structure of CD44 and assessment of the resulting functions. However, even greater structural variation is naturally introduced by CD44-bearing cells. A structural model is now available for the portion of CD44 that recognizes hyaluronan, but it is clear that all domains of the molecule influence CD44 functions.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9330866 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Adv Cancer Res. 1997;71:241-319.
CD44: structure, function, and association with the malignant process.
Naor D, Sionov RV, Ish-Shalom D.
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
CD44 is a ubiquitous multistructural and multifunctional cells surface adhesion molecule involved in cell-cell and cell-matrix interactions. Twenty exons are involved in the genomic organization of this molecule. The first five and the last 5 exons are constant, whereas the 10 exons located between these regions are subjected to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons, as well as variations in N-glycosylation, O-glycosylation, and glycosaminoglycanation (by heparan sulfate or chondroitin sulfate), generate multiple isoforms (at least 20 are known) of different molecular sizes (85-230 kDa). The smallest CD44 molecule (85-95 kDa), which lacks the entire variable region, is standard CD44 (CD44s). As it is expressed mainly on cells of lymphohematopoietic origin, CD44s is also known as hematopoietic CD44 (CD44H). CD44s is a single-chain molecule composed of a distal extracellular domain (containing, the ligand-binding sites), a membrane-proximal region, a transmembrane-spanning domain, and a cytoplasmic tail. The molecular sequence (with the exception of the membrane-proximal region) displays high interspecies homology. After immunological activation, T lymphocytes and other leukocytes transiently upregulate CD44 isoforms expressing variant exons (designated CD44v). A CD44 isform containing the last 3 exon products of the variable region (CD44V8-10, also known as epithelial CD44 or CD44E), is preferentially expressed on epithelial cells. The longest CD44 isoform expressing in tandem eight exons of the variable region (CD44V3-10) was detected in keratinocytes. Hyaluronic acid (HA), an important component of the extracellular matrix (ECM), is the principal, but by no means the only, ligand of CD44. Other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate. Mucosal addressin, serglycin, osteopontin, and the class II invariant chain (Ii) are additional, ECM-unrelated, ligands of the molecule. In many, but not in all cases, CD44 does not bind HA unless it is stimulated by phorbol esters, activated by agonistic anti-CD44 antibody, or deglycosylated (e.g., by tunicamycin). CD44 is a multifunctional receptor involved in cell-cell and cell-ECM interactions, cell traffic, lymph node homing, presentation of chemokines and growth factors to traveling cells, and transmission of growth signals. CD44 also participates in the uptake and intracellular degradation of HA, as well as in transmission of signals mediating hematopoiesis and apoptosis. Many cancer cell types as well as their metastases express high levels of CD44. Whereas some tumors, such as gliomas, exclusively express standard CD44, other neoplasms, including gastrointestinal cancer, bladder cancer, uterine cervical cancer, breast cancer and non-Hodgkin's lymphomas, also express CD44 variants. Hence CD44, particularly its variants, may be used as diagnostic or prognostic markers of at least some human malignant diseases. Furthermore, it has been shown in animal models that injection of reagents interfering with CD44-ligand interaction (e.g., CD44s- or CD44v-specific antibodies) inhibit local tumor growth and metastatic spread. These findings suggest that CD44 may confer a growth advantage on some neoplastic cells and, therefore, could be used as a target for cancer therapy. It is hoped that identification of CD44 variants expressed on cancer but not on normal cells will lead to the development of anti-CD44 reagents restricted to the neoplastic growth.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9111868 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pol Arch Med Wewn. 1996 Sep;96(3):297-302.
[CD44--cell receptor for hyaluronate. Clinical aspects of structure and function]
[Article in Polish]
Matysiak W.
Zakładu Immunologii Klinicznej Akademii Medycznej, Lublinie.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9122023 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: J Cell Sci. 1994 Sep;107 ( Pt 9):2353-9.
The role of the cytoplasmic domain in regulating CD44 function.
Isacke CM.
Department of Biology, Imperial College of Science, Technology and Medicine, London, UK.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7531197 [PubMed - indexed for MEDLINE]
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