Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation

Abstract

Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung. H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic. Conversely, fibroblasts stably expressing low levels of RHAMM as a result of antisense transfection are resistant to ras transformation. Collectively, these results indicate that RHAMM acts downstream of ras. The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan. These results provide evidence of the oncogenic potential of a novel extracellular matrix receptor and establish a functional link between transformation by ras and signaling within focal adhesions that are required for transformation by this oncogene.

Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region

“…These are similar to the modi®cations of Src occurring upon activation of the PDGF receptor (Ralston and Bishop, 1985), which reportedly re¯ect phosphorylation of residues in the amino terminus of Src and increased Src kinase activity (Gould and Hunter, 1988;Stover et al, 1996). Interestingly, Src activity has been associated with changes in cytoskeletal organization (Thomas et al, 1995;Parsons and Parsons, 1997;Brunton et al, 1997), such as those that might occur during the migration of cells (Hall et al, 1996;Boyer et al, 1997) and the retraction of neurites (Schindelholz et al, 1997).…”

“…In ®broblasts, Src has been implicated not only in carrying out the mitogenic e ects of PDGF (Twamley-Stein et al, 1993b) by activating a pathway that leads to increased Myc transcription , but also in organizing the cytoskeleton (Thomas et al, 1995) and mediating cell locomotion (Hall et al, 1996). In epithelial cells, on the other hand, Src has been shown to mediate cell scattering and morphological changes, but not mitogenic e ects (Warren et al, 1988;Rodier et al, 1995;Boyer et al, 1997).…”

A role for epidermal growth factor receptor, c-Src and focal adhesion kinase in an in vitro model for the progression of colon cancer

“…Transient phosphorylation of FAK has been linked to increased motility in ®broblasts stimulated with hyaluronan (Hall et al, 1994) and to an increase in migration and invasion of squamous cell carcinoma cells treated with hepatocyte growth factor (Matsumoto et al, 1994), which are both potent motogens. Furthermore increased expression of FAK has been found in invasive tumours of both the breast and colon (Owens et al, 1995).…”

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

“…3 RHAMM is involved in cell motility and signaling 6 as well as oncogenic events. 7 The mitogen-activated protein kinase (MAPK) pathway includes several families of signal transduction cascades which mediate information provided by extracellular stimuli. 8 The MAPK pathway is considered to be important for cellular growth, development and differentiation and regulates cell proliferation, apoptosis, cell differentiation and tissue development.…”