Current Perspectives on Awareness Information to Support Real-Time Communication

Abstract-Sharing awareness information to help remote people establish real-time communication has been a research area for the past couple decades. Much of the work so far has focused on sharing awareness for communication availability in the work setting. Yet several recent trends suggest the need to reconsider the contexts and assumptions around awareness research. Increasing deployment of communication technology in homes and the blurring of home and work boundaries means that more communication interactions involve the home. The popularity of mobile smartphones adds the mobile context and the sensor capabilities integrated into mobile devices. Given the broadened scope of where and how communication occurs and the importance of being able to smoothly negotiate starting and ending conversations, there is an opportunity to reconsider awareness research in today's environment. We identify current challenges and opportunities in awareness research from perspectives beyond focusing just on the workplace to include technologies and use practices in the home and mobile contexts. Keywords-awareness; availability; presence; awareness; computer-mediated communication; workplace; home; mobile I. RECONSIDERING AWARENESS INFORMATION For the past couple decades, research on presence and awareness has explored how to help people time and negotiate their attempts to establish communication over distance. Yet during the course of those years, much of the technology and use practice landscape has changed in ways that have a direct impact on how people use and interpret awareness information. The increased use of computer-mediated communication (CMC) in the home adds a distinctly different context in which to establish communication. The growing popularity of mobile smartphones not only adds a mobile context for establishing communication, but also offers new sensing capabilities that increases the amount of awareness information available. In light of these recent developments, we identify several important dimensions for reconsidering awareness information to support real-time communication. A. Awareness in the Workplace Context Much of the prior awareness research has focused on workbased communication, typically in the office setting of a work environment. For example, the early Media Space work Hudson et al. [4] conducted an Experience Sampling Method study to identify what are the strongest indicators for availability in the workplace. They concluded that the presence of speech (i.e., that a person was already engaged in conversation with someone else) was strongly correlated with being unavailable for new interaction. Sophisticated models for predicting presence and availability based on on-line calendar and computer activity information that is readily available have also been developed in the work context [5], [6]. More recently, Dugan et al. Sharing awareness in the workplace can leverage many resources and conditions that are typical of a work environment. The traditionally higher performance computin

Negative regulation of ErbB family receptor tyrosine kinases

Receptors of the EGF receptor or ErbB family of growth factor receptor tyrosine kinases are frequently overexpressed in a variety of solid tumours, and the aberrant activation of their tyrosine kinase activities is thought to contribute to tumour growth and progression. Much effort has been put into developing inhibitors of ErbB receptors, and both antibody and small-molecule approaches have exhibited clinical success. Recently, a number of endogenous negative regulatory proteins have been identified that suppress the signalling activity of ErbB receptors in cells. These include intracellular RING finger E3 ubiquitin ligases such as cbl and Nrdp1 that mediate ErbB receptor degradation, and may include a wide variety of secreted and transmembrane proteins that suppress receptor activation by growth factor ligands. It will be of interest to determine the extent to which tumour cells suppress these pathways to promote their progression, and whether restoration of endogenous receptor-negative regulatory pathways may be exploited for therapeutic benefit

EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism

Tumor cells often subvert normal regulatory mechanisms of signal transduction. This study shows this principle by studying yet uncharacterized mutants of the epidermal growth factor receptor (EGFR) previously identified in glioblastoma multiforme, which is the most aggressive brain tumor in adults. Unlike the well-characterized EGFRvIII mutant form, which lacks a portion of the ligand-binding cleft within the extracellular domain, EGFRvIVa and EGFRvIVb lack internal segments distal to the intracellular tyrosine kinase domain. By constructing the mutants and by ectopic expression in naive cells, we show that both mutants confer an oncogenic potential in vitro, as well as tumorigenic growth in animals. The underlying mechanisms entail constitutive receptor dimerization and basal activation of the kinase domain, likely through a mechanism that relieves a restraining molecular fold, along with stabilization due to association with HSP90. Phosphoproteomic analyses delineated the signaling pathways preferentially engaged by EGFRvIVb-identified unique substrates. This information, along with remarkable sensitivities to tyrosine kinase blockers and to a chaperone inhibitor, proposes strategies for pharmacological interception in brain tumors harboring EGFRvIV mutations.Goldhirsh FoundationNational Cancer Institute (U.S.) (CA118705)National Cancer Institute (U.S.) (CA141556)National Cancer Institute (U.S.) (U54-CA112967

The role of ubiquitination and hepatocyte growth factor-regulated tyrosine kinase substrate in the degradation of the adrenomedullin type I receptor

Calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 2 (RAMP2) comprise a receptor for adrenomedullin (AM). Although it is known that AM induces internalization of CLR•RAMP2, little is known about the molecular mechanisms that regulate the trafficking of CLR•RAMP2. Using HEK and HMEC-1 cells, we observed that AM-induced activation of CLR•RAMP2 promoted ubiquitination of CLR. A mutant (CLRΔ9KR), lacking all intracellular lysine residues was functional and trafficked similar to the wild-type receptor, but was not ubiquitinated. Degradation of CLR•RAMP2 and CLRΔ9KR•RAMP2 was not dependent on the duration of AM stimulation or ubiquitination and occurred via a mechanism that was partially prevented by peptidase inhibitors. Degradation of CLR•RAMP2 was sensitive to overexpression of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), but not to HRS knockdown, whereas CLRΔ9KR•RAMP2 degradation was unaffected. Overexpression, but not knockdown of HRS, promoted hyperubiquitination of CLR under basal conditions. Thus, we propose a role for ubiquitin and HRS in the regulation of AM-induced degradation of CLR•RAMP2

Voluntary ethanol consumption in male adolescent hamsters increases testosterone and aggression

The immediate and long-term biologic and behavioral consequences of voluntary ethanol (EtOH) exposure during male adolescence are unknown. In the present study, male golden hamsters voluntarily drank from a 15% EtOH solution in addition to consuming dry laboratory chow and water ad lib from Postnatal Day 25 to Postnatal Day 43. Over this adolescent period, they drank an average of 13 g/kg/day of EtOH, resulting in a mean blood EtOH concentration of ca. 53 mg %. On Postnatal Day 35, a period of enhanced sensitization and activation of the gonadal axis, testosterone levels were twice as high in EtOH animals than in sucrose-yoked controls. However, this difference disappeared by Postnatal Day 53, as EtOH and control animals showed comparable adult levels of plasma testosterone. When tested for aggression several days after the cessation of EtOH exposure, hamsters showed enhanced attack behavior toward smaller intruders placed into their home cage. These results suggest that voluntary EtOH exposure during male adolescence has specific neuroendocrine effects with lasting behavioral consequences

Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases

When appended to the epidermal growth factor receptor ( EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases

Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4

Ligand-dependent endocytosis of the epidermal growth factor receptor (EGFR) involves recruitment of a ubiquitin ligase, and sorting of ubiquitylated receptors to lysosomal degradation. By studying Hgs, a mammalian homolog of a yeast vacuolar-sorting adaptor, we provide information on the less understood, ligand- independent pathway of receptor endocytosis and degradation. Constitutive endocytosis involves receptor ubiquitylation and translocation to Hgs-containing endosomes. Whereas the lipid- binding motif of Hgs is necessary for receptor endocytosis, the ubiquitin-interacting motif negatively regulates receptor degradation. We demonstrate that the ubiquitin-interacting motif is endowed with two functions: it binds ubiquitylated proteins and it targets self-ubiquitylation by recruiting Nedd4, an ubiquitin ligase previously implicated in endocytosis. Based upon the dual function of the ubiquitin- interacting motif and its wide occurrence in endocytic adaptors, we propose a ubiquitin-interacting motif network that relays ubiquitylated membrane receptors to lysosomal degradation through successive budding events