Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway

Abstract

CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate–responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlying mechanism, we have found that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that cells expressing CD44ICD produce high levels of CD44 messenger RNA, suggesting that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel CD44 signaling pathway and shed new light on the functional link between proteolytic processing of an adhesion molecule at the cell surface and transcriptional activation in the nucleus.

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

“…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. [23][24][25][26][27] Despite knowing the role that CD44 -HA plays in promoting BC invasion and metastasis, the underlying downstream signaling mechanism is nascent.…”

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

“…Previous data showed that CD44-ICD stimulates p300-mediated transactivation (33). Thus, we cotransfected CD44-ICD with p300 or a p300-dominant negative construct (LYRR; ref.…”

CD44 in hematological neoplasias

“…(ii)Cleavage and subsequently translocation of the cytoplasmic tail of CD44 into the nucleus followed by transcription of several target genes inclusive the CD44 gene itself [57]. and enhanced cell motility [59].…”