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Activities of the tumour necrosis factor (TNF) family members are associated with their targeting to lipid rafts, specialised regions of the plasma membrane. Herein, we investigated the physical association of TNF and its family members cluster of differentiation 40 ligand (CD40L) and tumour necrosis factor‐related apoptosis‐inducing ligand with caveolin‐1, a lipid raft resident protein. We discovered that the intracellular domains of TNF and CD40L interact with caveolin‐1, and the membrane proximal region of TNF is required for the binding of caveolin‐1 domains. Full‐length TNF can form a complex with caveolin‐1 in membrane rafts of HeLa cells, and caveolin‐1 knockdown leads to impaired TNF transport to rafts. These findings provide the first evidence of a direct interaction between TNF, CD40L and caveolin‐1 and suggest that caveolin‐1 may be responsible for recruiting TNF to lipid rafts. [ABSTRACT FROM AUTHOR]

Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme and is responsible for the synthesis of cholesterol and fatty acids. We have previously shown that AACS is cleaved by legumain, a lysosomal asparaginyl endopeptidase. In this study, we attempted to determine the cleavage site of AACS. Mutagenesis analysis of AACS revealed that Asn547 is the specific cleavage site of AACS in mouse livers. The cleaved form of AACS (1-547) lost the ability to convert acetoacetate to acetoacetyl-CoA. Moreover, hydrodynamicsbased gene transduction showed that overexpression of AACS (1-547) increases the protein expression of caveolin-1, the principal component of the caveolae. These results suggest that cleavage of AACS by legumain is critical for the regulation of enzymatic activity and results in gain-of-function changes. [ABSTRACT FROM AUTHOR]

Highlights: [•] SMAD4 docks to the cell membrane in the presence of TGF-β1. [•] SMAD4 displays two subpopulations with different membrane docking behaviors, which are regulated by clathrin and caveolin-1. [•] The subpopulations have opposing roles in the nuclear shuttling of SMAD4 and the subsequent transcriptional regulation. [ABSTRACT FROM AUTHOR]

Abstract: The alterations of integrin glycosylation play a crucial role in tumor metastasis. Our previous studies indicated that caveolin-1 promoted the expression of the key α2,6-sialytransferase ST6Gal-I and fibronectin-mediated adhesion of mouse hepatocarcinoma cell. Herein, we investigated the role of α2,6-sialylated α5-integrin in the adhesion of mouse hepatocarcinoma H22 cell. We demonstrated that caveolin-1 up-regulated cell surface α2,6-linked sialic acid via stimulating ST6Gal-I transcription. Cell surface α2,6-sialylation was required for integrin α5β1-dependent cell adhesion to fibronectin, and an increase in α2,6-linked sialic acid on α5-subunit facilitated fibronectin-mediated focal adhesion kinase phosphorylations, suggesting that α2,6-sialylated α5-subunit promoted integrin α5β1-dependent cell adhesion. [Copyright &y& Elsevier]

Abstract: Caveolin-1, and probably also -2 and -3, can organize multimolecular membrane complexes involved in transmembrane traffic, cell adhesion and signal transduction. In this review, we discuss on the importance of caveolin membrane environment in regulating the architecture and function of such complexes, with a special emphasis on the role of sphingolipids. [Copyright &y& Elsevier]

Abstract: The small GTP-ase Rac-1 can trigger p38 MAPK activation and, in turn, p38α can regulate signalling pathways that potentially impinge on Rac-1 activity. We have investigated the cross-talk between p38α and Rac-1 and found that p38α regulates the association between Rac-1 and caveolin-1 in serum-deprived cardiomyocytes. This interaction depends on cell attachment and correlates with higher levels of active Rac-1. Actin organization might regulate the formation of Rac-1–caveolin-1 complexes. In contrast, the Rac-1–caveolin-1 interaction is almost undetectable in the presence of serum, where Rac-1 activity is negatively regulated by p38α. Our results indicate that p38α can differentially contribute to Rac-1 activation depending on the presence of serum. [Copyright &y& Elsevier]

Abstract: The role of caveolae and the caveolin proteins in cancer has been the subject of extensive research. BRCA1 participates in multiple biological pathways including DNA damage repair, transcriptional control, cell growth, apoptosis, and others. Little information, however, is available regarding the cellular mechanisms that control BRCA1 gene expression. The present study examined the potential regulation of BRCA1 gene expression and subcellular localization by Cav-1. Results of Western blots, RT-PCR, and transfection experiments showed that Cav-1 enhances BRCA1 protein and mRNA levels via a mechanism that involves transactivation of the BRCA1 promoter and which is p53-dependent. In addition, immunostaining experiments demonstrate that Cav-1 induced the cytoplasmic sequestration of BRCA1. [Copyright &y& Elsevier]

Caveolin-1, the principal component of caveolae, is a 21–24 kDa integral membrane protein. The interaction of the caveolin-1 scaffolding domain with signaling molecules can functionally inhibit the activity of these signaling proteins. Little is known about how caveolin-1 influences the expression of P-glycoprotein (P-gp), an ABC transporter encoded by multi-drug resistance (MDR1) gene. To elucidate the possible mechanism between caveolin-1 and P-gp expression, in the present study, we overexpressed caveolin-1 in the Hs578T/Dox breast adenocarcinoma cells, a multidrug resistant line, and then selected single clone cells highly expressing caveolin-1 level. Both Western blot and confocal microscopy analyses showed that caveolin-1 was markedly overexpressed in the transfectants, while P-gp protein was almost abolished. Reverse transcription polymerase chain reaction also showed that the expression of P-gp mRNA was significantly suppressed in the transfectants. It was confirmed further by Northern blot analysis. Moreover, through measuring the changes of drug resistance and P-gp transport activity in the transfectants, we found that overexpression of caveolin-1 reversed drug resistance of transfectants and lowered their P-gp transport activity to the level of Hs578T/S. Taken together, our results indicate that such suppression of P-gp in the transfectants overexpressing caveolin-1 may occur at the transcriptional level. [Copyright &y& Elsevier]

Caveolins have been identified as key components of caveolae, specialized cholesterol-enriched raft domains visible as small flask-shaped invaginations of the plasma membrane. In polarized MDCK cells caveolin-1 and -2 are found together on basolateral caveolae whereas the apical membrane, where only caveolin-1 is present, lacks caveolae. Expression of a caveolin mutant prevented the formation of the large caveolin-1/-2 hetero-oligomeric complexes, and led to intracellular retention of caveolin-2 and disappearance of caveolae from the basolateral membrane. Correspondingly, in MDCK cells over-expressing caveolin-2 the basolateral membrane exhibited an increased number of caveolae. These results indicate the involvement of caveolin-2 in caveolar biogenesis. [Copyright &y& Elsevier]