The urokinase receptor and integrins in cancer progression

Enhanced levels of expression of urokinase receptor (uPAR) and certain integrins have been linked to cancer cell progression. This has classically been attributed to matrix degradation via the activation of the urokinase (uPA)/plasmin system and modulation of cell motility and survival through integrin engagement. More recently, uPAR has been shown to play multiple roles independent of protease activity. Specifically, uPAR has been shown to be intimately involved in the regulation of cell adhesion, migration and proliferation in part through interactions with other membrane partners, including integrins. The goal of this review is to summarize recent insights in the function of uPAR/integrin interactions, to provide a framework for understanding the importance of these interactions in the context of cancer, and to highlight its potential as a target for therapeutic intervention.     

The utility F-box for protein destruction

A signature feature of all living organisms is their utilization of proteins to construct molecular machineries that undertake the complex network of cellular activities. The abundance of a protein element is temporally and spatially regulated in two opposing aspects: de novo synthesis to manufacture the required amount of the protein, and destruction of the protein when it is in excess or no longer needed. One major route of protein destruction is coordinated by a set of conserved molecules, the F-box proteins, which promote ubiquitination in the ubiquitin-proteasome pathway. Here we discuss the functions of F-box proteins in several cellular scenarios including cell cycle progression, synapse formation, plant hormone responses, and the circadian clock. We particularly emphasize the mechanisms whereby F-box proteins recruit specific substrates and regulate their abundance in the context of SCF E3 ligases. For some exceptions, we also review how F-box proteins function through non-SCF mechanisms.     

Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives

Beside its role as a neurotransmitter in the central nervous system, serotonin appears to be a central physiologic mediator of many gastrointestinal (GI) functions and a mediator of the brain-gut connection. By acting directly and via modulation of the enteric nervous system, serotonin has numerous effects on the GI tract. The main gut disturbances in which serotonin is involved are acute chemotherapy-induced nausea and vomiting, carcinoid syndrome and irritable bowel syndrome. Serotonin also has mitogenic properties. Platelet-derived serotonin is involved in liver regeneration after partial hepatectomy. In diseased liver, serotonin may play a crucial role in the progression of hepatic fibrosis and the pathogenesis of steatohepatitis. Better understanding of the role of the serotonin receptor subtypes and serotonin mechanisms of action in the liver and gut may open new therapeutic strategies in hepato-gastrointestinal diseases. Received 15 August 2007; received after revision 1 November 2007; accepted 5 November 2007     

Highly homologous HERC proteins localize to endosomes and exhibit specific interactions with hPLIC and Nm23B

Small HERC proteins are defined by the presence of one RCC1-like domain and a HECT domain. Having evolved out of one common ancestor, the four members of the family exhibit a high degree of homology in genomic organization and amino acid sequence, thus it seems possible that they might accomplish similar functions. Here we show that small HERC proteins interact with each other and localize to the same cellular structures, which we identify as late endosomes and lysosomes. We demonstrate interaction of HERC3 with the ubiquitin-like proteins hPLIC-1 and hPLIC-2 and we establish interaction of HERC5 with the metastasis suppressor Nm23B. While hPLIC proteins are not ubiquitinated by HERC3, HERC5 plays an important role in ubiquitination of Nm23B. In summary, although small HERC proteins are highly homologous showing the same subcellular distribution, they undergo different molecular interactions.     

Considerations on Temperature, Longevity and Aging

A modest reduction in body temperature prolongs longevity and may retard aging in both poikilotherm and homeotherm animals. Some of the possible mechanisms mediating these effects are considered here with respect to major aging models and theories.     

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.     

Dissection of a novel molecular determinant mediating Golgi to trans-Golgi network transition

Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal consisting of the amino acids E₅P₆ in gal-T1 and D₂P₃ in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008     

Olfactory receptor trafficking to the plasma membrane

Olfactory receptors typically exhibit poor plasma membrane localization and functionality when heterologously expressed in most cell types. It has therefore proven difficult to effectively study olfactory receptor pharmacology and signaling mechanisms using traditional cell culture systems. Over the past few years, a variety of distinct proteins have been reported to interact with olfactory receptors and facilitate olfactory receptor trafficking to the plasma membrane in heterologous cells. Advances in this area have shed significant light on the fundamental factors governing the cell-specific control of olfactory receptor trafficking.     

Zinc binding to peptide analogs of the structural zinc site in alcohol dehydrogenase: Implications for an entatic state

Zinc binding to the peptide replica and analogs to residues 93–115 of horse liver alcohol dehydrogenase (ADH) was examined by competition of the peptides and the chromophoric chelator 4-(2- pyridylazo)resorcinol for zinc and X-ray absorption fine structure analysis of the zinc ligands. In the enzyme, zinc is coordinated by four Cys residues. In the peptide replica, zinc is bound to three Cys and one His residue. A four-Cys zinc coordination is observed only when His is removed, leading to increased zinc stability. ADH crystal structures reveal that the ε-amino group of the conserved residue Lys323 is within H-bond distance of the backbone amide oxygens of residues 103, 105 and 108, likely stabilizing the zinc coordination in the enzyme. The peptide data thus indicate structural strain and increased energy in the zinc-binding site in the protein, characteristic of an entatic state, implying a functional nature for this zinc site. Received 3 July 2008; received after revision 11 August 2008; accepted 1 September 2008