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Objective: The CD44 transmembrane glycoprotein family has been implicated in the growth and metastasis of numerous human cancers. CD44 may function in some cells through interactions with type I receptor tyrosine kinases, including erbB2. Here, we tested whether CD44 interacts with erbB2 and another type I receptor, the epidermal growth factor receptor (EGFR), in human cervical carcinoma tissues and cell lines and whether these interactions influence erbB2 signaling., Methods: CD44, EGFR, and erbB2 colocalization were examined in 36 pT1b-pT2b cervical cancer cases and in the CaSki and SiHa cervical carcinoma cell lines by immunohistochemistry and laser scanning confocal microscopy. The role of CD44-EGFR-erbB2 interactions in erbB2 signaling was examined by immunoprecipitation and using antisense CD44 oligonucleotides., Results: CD44, erbB2, and EGFR coexpression and colocalization were observed in 42% (15/36) of cervical carcinoma cases and in both cervical carcinoma cell lines. Colocalization occurred to an equivalent extent in all tumor grades examined. CD44 coimmunoprecipitated with erbB2 and EGFR in cervical carcinoma cell lysates, indicating that these proteins interact with each other. Reduction of CD44 expression inhibited constitutive erbB2 activity. High CD44 expression was linked to EGFR activity using dominant negative EGFR, suggesting that type I receptors may autoregulate their activity in these cells., Conclusions: Our data indicate that CD44 can mediate type I receptor function in cervical carcinoma cells that overexpress both CD44 and either erbB2 or EGFR and suggest a novel mechanism by which these proteins may contribute to cervical carcinoma tumor growth and metastasis., (Copyright 2001 Academic Press.)