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CD44: From adhesion molecules to signalling regulators

Key Points

  • Members of the CD44 transmembrane protein family have functions in many processes in normal life (for example, in haematopoiesis, the immune system and organogenesis), and in pathological situations (for example, cancer and metastasis).

  • The functions of the CD44 proteins seem to be substituted by other proteins in mice that have a disrupted CD44 gene, and the diverse biological functions can be reduced to three molecular mechanisms of action.

  • First, CD44 can undergo passive or regulated ligand binding. This includes adhesion to hyaluronan and other components of the extracellular matrix, as well as axon deterrence and action as a scaffold for enzymes and growth factors.

  • Second, CD44 can have co-receptor functions that mediate signalling by receptor tyrosine kinases. This function is important for at least a small group of receptor tyrosine kinases, which includes Met and members of the ERBB family of receptor tyrosine kinases.

  • Third, CD44 can provide a link between the plasma membrane and the actin cytoskeleton through binding to ERM proteins.

  • These three molecular actions enable us to explain how CD44 proteins act in a switch between promoting and arresting the growth of cells, and why they trigger metastasis formation in some tumours but act as tumour suppressors in others.

Abstract

Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes — not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.

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Figure 1: CD44 transcripts and proteins.
Figure 2: Molecular actions of CD44.
Figure 3: Control of cell growth and growth arrest by CD44.

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Acknowledgements

We thank C. Isacke, D. Jackson and V. Orian-Rousseau for their critical reading and helpful suggestions.

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Correspondence to Peter A. Herrlich.

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DATABASES

OMIM

neurofibromatosis type 2

Swiss-Prot

CD44

DAL1

DBL

E-cadherin

ERBB1

ERBB2

ERBB3

ERBB4

ezrin

FGF receptor 4

FYN

HBEGF

LCK

merlin

Met

MMP2

MMP7

MMP9

moesin

OPN

PAK2

radixin

SF/HGF

TIAM1

VAV2

Glossary

INTEGRIN

A cell-surface protein complex that is composed of α- and β-subunits that are important for cell–cell and cell–extracellular-matrix adhesion.

CADHERIN

A cell-adhesion molecule that is responsible for strong cell–cell contacts through homophilic interaction.

RECEPTOR TYROSINE KINASE

A transmembrane receptor, the intracellular domain of which has intrinsic tyrosine phosphorylation activity.

ALTERNATIVE SPLICING

The regulated alternative usage of exons during pre-mRNA splicing.

HYALURONAN

A high-molecular-weight linear polysaccharide that is composed of repeating units of D-glucuronate (1-β-3) and N-acetyl-D-glucosamine (1-β-4).

GLYCOSAMINOGLYCAN

(GAG). A polysaccharide that is composed of alternate residues of uronic acid and hexosamine. Glycosaminoglycans link to a protein core to form a proteoglycan.

LIPID RAFT

A detergent-resistant cholesterol-rich microdomain of the plasma membrane that is thought to foster the association of cooperating proteins.

BAND 4.1 SUPERFAMILY

A large group of proteins, some of which (for example ezrin, radixin and moesin (ERM)) bind to actin. The 4.1 protein itself binds to spectrin.

MERLIN

A member of the band 4.1 superfamily with homology to the ERM proteins. Synonymous with schwannomin (for its involvement in schwannoma formation) and NF2, the gene mutated in neurofibromatosis type 2 (NF2) patients.

MET

A tyrosine kinase receptor that binds scatter factor/hepatocyte growth factor (SF/HGF). It functions in differentiation, invasive growth and morphogenesis.

FILAMENTOUS ACTIN

(F-actin). A component of the cytoskeleton. It is the polymerized form of monomeric G-actin.

VASCULAR LEAK SYNDROME

Increased blood capillary leak, most likely due to endothelial damage by cytotoxic T cells.

MATRIX METALLOPROTEINASE

A zinc-containing proteolytic enzyme that degrades components of the extracellular matrix.

LEUKOCYTE ROLLING

The first of a two-step mechanism by which white blood cells adhere to the endothelium. Before they adhere firmly (the second step, which is integrin mediated), leukocytes 'roll' inside vessels, making transient attachments that are mediated primarily by selectins.

HEPARAN-SULPHATE PROTEOGLYCAN

A protein that is modified by heparan-sulphate side chains.

ERBB PROTEIN FAMILY

A group of proteins (ERBB1–4) that are related to the epidermal-growth-factor receptor.

OSTEOPONTIN

(OPN). A component of the extracellular matrix that is involved in inflammation, tissue remodelling and cell survival.

NEUREGULIN

A ligand for ERBB2– ERBB3 heterodimers.

T-CELL-RECEPTOR CAPPING

The extensive clustering of T-cell receptors (TCRs) as a consequence of TCR activation.

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Ponta, H., Sherman, L. & Herrlich, P. CD44: From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4, 33–45 (2003). https://doi.org/10.1038/nrm1004

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