Heparan Sulfate-modified CD44 Promotes Hepatocyte Growth Factor/Scatter Factor-induced Signal Transduction through the Receptor Tyrosine Kinase c-Met

Abstract

CD44 has been implicated in tumor progression and metastasis, but the mechanism(s) involved is as yet poorly understood. Recent studies have shown that CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and functional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway mediates cell growth and motility and has been implicated in tumor invasion and metastasis. We demonstrate that a CD44v3 splice variant efficiently binds HGF/SF via its heparan sulfate side chain. To address the functional relevance of this interaction, Namalwa Burkitt's lymphoma cells were stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ERK1 and -2. By heparitinase treatment and the use of a mutant HGF/SF with greatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties. Our results identify heparan sulfate-modified CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating and presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration might be instrumental in promoting tumor growth and metastasis.

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

“…10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target genes such as CD44 itself. 21,22 CD44 and its variants can induce chemoresistance and invasion of human BC cell lines via different mechanisms.…”

CD44 Regulates Arteriogenesis in Mice and Is Differentially Expressed in Patients With Poor and Good Collateralization

“…Interestingly, these decreased protein levels in CD44 Ϫ/Ϫ mice were accompanied by increased mRNA levels. Because it has been shown that certain CD44 isoforms can bind growth factors and protect them from proteolysis by extracellular proteinases, [15][16][17]27 this finding suggests that decreased growth factor stability contributes to the deficient arteriogenic phenotype of CD44 Ϫ/Ϫ mice.…”

“…CD44 binds and presents these factors to their high-affinity receptors and promotes signaling and stability by protecting them from degradation. [15][16][17] In the present study, we therefore explored the role of CD44 during arteriogenesis and provide the first direct evidence for involvement of this receptor in collateral artery formation.…”

Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells

“…They described that these HS-GAGs indeed had differential binding capacities to SDF-1. Van der Voort et al 47 recently showed that cell surface HSPGs on activated B cells could bind hepatocytic growth factor but not SDF-1. This illustrates that HS is variable in structure and SDF-1 binding.…”