Orian-Rousseau V, Chen L, Sleeman JP et al.CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16:3074-86

Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany.
Genes & Development (Impact Factor: 10.8). 01/2003; 16(23):3074-86. DOI: 10.1101/gad.242602
Source: PubMed

ABSTRACT The tyrosine kinase receptor c-Met and its ligand HGF/SF, ezrin, and splice variants of CD44 have independently been identified as tumor metastasis-associated proteins. We now show that these proteins cooperate. A CD44 isoform containing variant exon v6 sequences is strictly required for c-Met activation by HGF/SF in rat and human carcinoma cells, in established cell lines as well as in primary keratinocytes. CD44v6-deficient tumor cells were unable to activate c-Met unless they were transfected with a CD44v6-bearing isoform. Antibodies to two v6-encoded epitopes inhibited autophosphorylation of c-Met by interfering with the formation of a complex formed by c-Met, CD44v6, and HGF/SF. In addition, signal transduction from activated c-Met to MEK and Erk required the presence of the cytoplasmic tail of CD44 including a binding motif for ERM proteins. This suggests a role for ERM proteins and possibly their link to the cortical actin cytoskeleton in signal transfer.

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    • "A recent study showed that the switch of CD44s to CD44v6 can promote the development of a normal mammary gland into carcinoma [54]. Furthermore, it has been shown that CD44v6 and CD44v9 can increase invasion and metastasis via cooperating with c-Met to activate the MEK and Erk signaling pathways [55] and can increase antiapoptotic ability via inhibiting Fas signaling [56]. In the present study, we found that CD44v6+, CD44v9+ and CD44s− significantly decreased the survival rate of pancreatic carcinoma patients. "
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    ABSTRACT: Background and purpose: CD44 variants have been associated with tumor invasion and metastasis, but CD44 expression patterns have not been systematically investigated in pancreatic carcinoma. This study systematically investigated whether CD44 expression patterns are involved in pancreatic carcinoma metastasis and prognosis. We applied primers specific for all CD44 variants and CD44s to analyze the expression patterns of CD44 (CD44v2-CD44v10 and CD44s) using quantitative real-time PCR (qRT-PCR). We then further evaluated their roles in pancreatic carcinoma metastasis and prognosis using clinical survival analysis. Increased CD44v expression and decreased CD44s expression were found in metastatic pancreatic carcinoma in three different cell lines and in human tumor tissue. Clinical analysis showed that CD44v6+ and CD44v9+ were correlated with lymph node metastasis, liver metastasis and TNM stage. However, CD44s- was associated with liver metastasis, tumor differentiation and TNM stage. Survival analysis showed that patients with CD44v6+/CD44s- or CD44v6+/CD44s- had lower overall survival (OS) rates, although the individual expression of CD44v6, CD44v9 and CD44s was also related to decreased OS rates. Univariate analysis showed that lymph node metastasis; vessel invasion; hepatic metastases; TNM stage; and individual or co-expression of CD44v6, CD44v9 and CD44s were risk factors affecting survival. Multivariate analysis showed that CD44v6+/CD44s- was an independent predictor of survival. We found that CD44v6+, CD44v9+ and CD44s- were associated with pancreatic carcinoma metastasis and progression and that CD44v6+/CD44s- was an independent risk factor affecting survival in pancreatic carcinoma. Therefore, the different expression patterns of CD44v/CD44s may determine pancreatic carcinoma prognosis.Virtual slides: The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 04/2014; 9(1):79. DOI:10.1186/1746-1596-9-79 · 2.60 Impact Factor
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    • "Only CD44v3 is decorated by heparin sulphate enabling it to bind growth and angiogenic factors including VEGF, bFGF and HGF. However, the CD44v6 has also been demonstrated to function as a co-receptor for receptor tyrosine kinase c-Met on epithelial cells [75], and to co-operate with VEGFR-2-mediated angiogenesis in endothelial cells [76]. The expression of standard isoform of CD44 dominates on TIME cells and most likely mediates the effects on angiogenesis, however, we knock-down all splice forms of CD44, therefore specific functions of the variant splice forms of CD44 cannot be excluded. "
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    ABSTRACT: A striking feature of microvascular endothelial cells is their capacity to fuse and differentiate into tubular structures when grown in three-dimensional (3D) extracellular matrices, in collagen or Matrigel, mimicking the in vivo blood vessel formation. In this study we demonstrate that human telomerase-immortalised foreskin microvascular endothelial (TIME) cells express high levels of the hyaluronan receptor CD44 and the hyaluronidase HYAL2. Knock-down of CD44 or HYAL2 resulted in an inability of TIME cells to form a tubular network, suggesting a key regulatory role of hyaluronan in controlling TIME cell tubulogenesis in 3D matrices. Knock-down of CD44 resulted in an upregulation of mRNA expression of the chemokines CXCL9 and CXCL12, as well as their receptors CXCR3 and CXCR4. This was accompanied by a defect maturation of the tubular structure network and increased phosphorylation of the inhibitor of NFκB kinase (IKK) complex and thus translocation of NFκB into the nucleus and activation of chemokine targed genes. Furthermore, the interaction between CD44 and hyaluronan determines the adhesion of breast cancer cells. In summary, our observations support the notion that the interaction between CD44 and hyaluronan regulates microvascular endothelial cell tubulogenesis by affecting the expression of cytokines and their receptors, as well as breast cancer dissemination.
    PLoS ONE 03/2014; 9(3):e90921. DOI:10.1371/journal.pone.0090921 · 3.23 Impact Factor
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    • "Another important component of the HFG-Met signaling is the ubiquitous transmembrane glycoprotein CD44, the major receptor for hyaluronic acid [21,22]. In different cell types, the activation of the MET receptor by HGF depends on the presence of some isoforms of CD44 [21]. "
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    ABSTRACT: Via the hepatocyte growth factor receptor (Met), hepatocyte growth factor (HGF) exerts key roles involving skeletal muscle development and regeneration. Heparan sulfate proteoglycans (HSPGs) are critical modulators of HGF activity, but the role of specific HSPGs in HGF regulation is poorly understood. Glypican-1 is the only HSPG expressed in myoblasts that localize in lipid raft membrane domains, controlling cell responses to extracellular stimuli. We determined if glypican-1 in these domains is necessary to stabilize the HGF-Met signaling complex and myoblast response to HGF. C2C12 myoblasts and a derived clone (C6) with low glypican-1 expression were used as an experimental model. The activation of Met, ERK1/2 and AKT in response to HGF was evaluated. The distribution of Met and its activated form in lipid raft domains, as well as its dependence on glypican-1, were characterized by sucrose density gradient fractionation in both cell types. Rescue experiments reexpressing glypican-1 or a chimeric glypican-1 fused to the transmembrane and cytoplasmic domains of mouse syndecan-1 or myoblast pretreatment with MbetaCD were conducted. In vitro and in vivo myoblast migration assays in response to HGF were also performed. Glypican-1 localization in membrane raft domains was required for a maximum cell response to HGF. It stabilized Met and HGF in lipid raft domains, forming a signaling complex where the active phospho-Met receptor was concentrated. Glypican-1 also stabilized CD44 in a HGF-dependent manner. In addition, glypican-1 was required for in vitro and in vivo HGF-dependent myoblast migration. Glypican-1 is a regulator of HGF-dependent signaling via Met in lipid raft domains.
    Skeletal Muscle 02/2014; 4(1):5. DOI:10.1186/2044-5040-4-5
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