However, most variants are generated by alternative splicing of at least 12 exons, leading to changes in the core protein (7). These size differences can be partially attributed to posttranslational modifications, as all isoforms of CD44 are highly glycosylated (2). The CD44 molecule is known to display extensive size heterogeneity, ranging from the standard 85–95 kDa form (CD44s) to larger variant isoforms (CD44v) of 200 kDa or more. The complexity of CD44 function has been linked to its structure, although functional characterization of the different isoforms which constitute this family is still limited. The ability to suppress apoptosis might play a critical role in the onset and development of colorectal malignancies.ĬD44, the principle HA receptor in a variety of cell types (1, 2), plays a role in a diverse range of physiological and pathological processes, including cell-cell and cell-extracellular matrix interactions, cell migration, lymphocyte homing, leukocyte activation, hemopoiesis, presentation of chemokines and growth factors, and metastatic spread (reviewed in Refs. These results establish a novel role for CD44 in determining survival of colon carcinoma cells through lyn kinase and Akt. Moreover, overexpression of dominant-active lyn recapitulated chemoresistance via a pathway shown to involve activation of phosphoinositide 3-kinase and Akt. We observed that variant CD44 produced activation of the src-family tyrosine kinase lyn. Resistance was induced by monoclonal antibodies directed against epitopes independent of the hyaluronate-binding region but was not triggered by identical treatment of a carcinoma line expressing the standard CD44 isoform. Activation of variant CD44 in colon carcinoma cell lines triggered resistance to the drug 1,3-bis(2-chloroethyl)-1-nitrosurea. Enhanced expression of variant CD44 isoforms has been associated with aggressive tumor behavior, prompting the question of whether signaling from this receptor might modulate drug sensitivity. A major obstacle to successful treatment of colorectal cancer is chemotherapy resistance.

Lyn may before plastic