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First published online December 31, 2003
doi: 10.1242/10.1242/jcs.00954

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The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events

¹ The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
² Cambridge Antibody Technology, Milstein Building, Granta Park, Cambridge, CB1 6GH, UK

View larger version (53K): [in a new window]   Fig. 1. CD44 structure and sequence conservation. (A) Genomic organization of CD44. The human gene encoding CD44 consists of 20 exons and is located at 11p13. The exons encoding the hyaluronan-binding domain and transmembrane domain are cross-hatched and stippled, respectively. (B) mRNA splicing patterns in CD44. The standard form of CD44, CD44s, comprises exons 1-5, 16-18 and 20 (green). Most variant forms of CD44, CD44v, contain the standard exons with combinations of exons 6-15 (v1-v10) (orange). The inclusion of exon 19, normally absent in most CD44 transcripts, results in a CD44 short-tail variant owing to use of an alternative translation stop codon. (C) Cross-species sequence comparison of the CD44 transmembrane and cytoplasmic domains. Orthologous CD44 sequences (human, P16070; Papio hamadryas (baboon), P14745; Mus musculus (mouse), P15379; Rattus norvegicus (rat), P26051; Cricetulus griseus (chinese hamster), P20944; Mesocricetus auratus (golden hamster), Q60522; Canis familiaris (dog), Q28284; Bos taurus (cow), Q29423; Equus caballus (horse), Q05078; Capra hircus(goat), CD051825; Ceratotherium simum simum (rhinoceros), AF045939; Gallus gallus (chicken); AAD37443; Anas platyrhynchos (duck), AAK40246) were aligned using the ClustalW program (EBI). In reference to the human sequence, the identical, physicochemically conserved and non-conserved amino acid residues are shown in blue, yellow and red, respectively. Note that the dog sequence is incomplete. (D) Sequence features of the human CD44 transmembrane and cytoplasmic domains. The transmembrane domain (grey) contains two sites for regulated intramembranous cleavage (arrowheads). Several functional motifs have been identified including a FERM-binding domain (green), ankyrin-binding domain (brown) and a basolateral targeting motif (light blue). Other posttranslational modifications include phosphorylation on serine residues (blue) with a protein kinase C (PKC) site at Ser291, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) site at Ser325, and a predicted protein kinase A (PKA) site at Ser316. Palmitoylation is also known to occur, with prospective sites being Cys286 and Cys295 (orange). The cytoplasmic tail terminates in a potential PDZ-domain-binding peptide (magenta).

View larger version (34K): [in a new window]   Fig. 2. Proteolytic processing of CD44. The extracellular stem region of CD44 is proteolytically cleaved by MT1- and MT3-MMPs in addition to other CD44 sheddases, leaving a CD44 C-terminal fragment (CTF) embedded in the plasma membrane. The cleaved extracellular region is either secreted into the fluid phase or sequestered to the extracellular matrix. Extracellular domain cleavage is necessary for further processing of the CD44-CTF by regulated intramembranous proteolysis (RIP) by presenilin-1/-secretase activity. RIP processing results in the secretion of a CD44ß-like peptide and the generation of a CD44 intracellular domain fragment (ICD). The CD44-ICD has been shown to be involved in nuclear signalling.

View larger version (20K): [in a new window]   Fig. 3. Model for the regulation of the CD44-ERM complex by dynamic phosphorylation of the CD44 cytoplasmic tail. The ERM (ezrin, radixin, moesin)-family proteins can function to crosslink transmembrane receptors, including CD44, to the cytoskeleton. Their basic structure consists of the three-lobed N-terminal FERM domain followed by a coiled-coil region and a C-terminal domain that contains an F-actin binding site. In their `inactive' conformation, the C-terminal domain binds to the FERM domain, masking both transmembrane receptors and F-actin interaction sites. Conformational regulation between the `inactive' and `active' forms involves complex mechanisms including phosphorylation and binding to the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) (reviewed by Bretscher et al., 2002). The cytoplasmic tail of CD44 is phosphorylated at Ser325 by CaMKII and this form of the receptor binds to an `active' ERM protein that links CD44 to the actin cytoskeleton. PKC activation results in a concomitant dephosphorylation of Ser325 and phosphorylation of Ser291, resulting in disengagement of the ERM proteins and loss of cytoskeletal association.

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