EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44

Transportin Regulates Nuclear Import of CD44

“…Nuclear Localization of CD44-It has been shown that the intracellular domain of CD44 can be translocated to the nucleus (12) and that engagement of HA triggers endocytosis of the mature CD44 protein (8,21). To address the intracellular fate of CD44, we used MNNG/HOS osteosarcoma cells that constitutively express high levels of the standard 85-90-kDa CD44 isoform (CD44H).…”

“…We therefore asked whether hyaluronic acid binding could play the same role in vivo. To answer this question we used the CD44 R41A mutant, which is unable to bind HA (13), the dsp mutant lacking the signal peptide (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], and the intracellular domain of CD44 alone (ICD, starting with A669) (12). pMSCVhygro plasmids containing mutant CD44 were expressed in human melanoma MC cells, which have negligible levels of endogenous HA receptor (Fig.…”

“…Based on its diverse functions, CD44 is implicated in a range of physiological and pathological processes including normal development, inflammation, and cancer progression (7). Because it resides in lipid rafts in the cell membrane, CD44 serves not only as a receptor for extracellular matrix components, including HA, but as a co-receptor for receptor tyrosine kinases of the ErbB family (8) and Met (9). CD44 also plays a role in anchorage of the actin cytoskeleton to the plasma membrane, which is important for cell motility, and interacts with the ezrin-radixin-moesin family of cytoskeletal adaptors (10), as well as merlin (11), through which much of its most relevant signaling for cell motility and survival is believed to occur.…”

Transforming Growth Factor-β1 (TGF-β1)-stimulated Fibroblast to Myofibroblast Differentiation Is Mediated by Hyaluronan (HA)-facilitated Epidermal Growth Factor Receptor (EGFR) and CD44 Co-localization in Lipid Rafts

“…The HA receptor CD44 can function as a co-receptor, physically associating with several membrane-bound proteins, resulting in modulation of intracellular signal transduction pathways and facilitating the formation of specialized signaling complexes (46,47). In light of these reports, we sought to determine if a similar system operated during myofibroblast differentiation.…”

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

“…[19][20][21][22][23][24][25] Moreover, the overall response rate of women diagnosed with HER2-positive metastatic breast cancer and treated with trastuzumab as a single first-line agent is only 26%; that is, > 70% of HER2-overexpressing metastatic breast carcinomas show a resistance to trastuzumab ab initio. A variety of possible mechanisms of escape from trastuzumab appear to involve many of the same biomarkers that have been implicated in the biology of CS-like cells: e.g., the overexpression of the stem cell-related marker CD44, leading to a loss or blockage of the trastuzumab-binding site at the extracellular domain of HER2; 26,27 the upregulation of stem cell markers, such as CXCR4, β1 integrin or Notch-1, [28][29][30][31][32] leading to the activation of alternative pathways circumventing HER2 signaling and the upregulation of pro-survival mediators, such as the inhibitor of apoptosis survivin. 33 Accordingly, it has been suggested that, although trastuzumab effectively targets cancer-initiating cells, a clinical resistance to trastuzumab may counter-intuitively be driven by breast CSCs.…”