Down-regulation of activated signaling receptors in response to their ligands plays a key role in restricting the extent and duration of the signaling. Mechanisms underlying down-regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown. Here we show that IFNAR1 interacts with the Homolog of Slimb (HOS) F-box protein in a phosphorylation-dependent manner, and that this interaction is promoted by interferon a (IFNa). IFNAR1 is ubiquitinated by the Skp1-Cullin1-HOS-Roc1 (SCF HOS ) ubiquitin ligase in vitro. HOS expression and activities are required for IFNa-stimulated ubiquitination of IFNAR1, endocytosis of the type I interferon receptor, down-regulation of IFNAR1 levels, and IFNAR1 proteolysis via the lysosomal pathway. Furthermore, modulations of HOS activities affect the extent of Stat1 phosphorylation and Stat-mediated transcriptional activities as well as the extent of antiproliferative effects of type I interferons. These ®ndings characterize SCF HOS as an E3 ubiquitin ligase that is essential for ubiquitination, proteolysis and down-regulation of IFNAR1, and implicate HOS in the regulation of cellular responses to IFNa.

Background: CD44, a multifunctional receptor, undergoes cleavage to produce an intracytoplasmic domain (CD44-ICD) that translocates into the nucleus. Results: CD44-ICD binds to a novel DNA consensus sequence and activates many genes. Conclusion:We finally explain the multifunctionality of CD44 and reveal new genes affected by CD44. Significance: Our findings will accelerate the understanding of how CD44-ICD regulates a multitude of cell functions.

Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation. We also show that the Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. Thus, CD44 increases P-gp mediated drug resistance and represents a potential therapeutic target in P-gp-positive cells.

Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-A (TNF-A), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-A modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-A in CD44 expression of cancer cells. Recent clinical work using TNF-A inhibitors for the treatment of ovarian cancer makes the study of TNF-A interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-A on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-A differentially modulates the expression of CD44 in TNF-A-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-A up-regulation of CD44 expression was dependent on the activation of c-Jun NH 2 -terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-A failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.