Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase

SummaryHER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4 kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4 residues contacted by lapatinib are conserved in the EGF receptor and HER2/ErbB2, which lapatinib also targets. These results demonstrate that key elements of kinase activation and inhibition are conserved among ErbB family members

Pathways to Belonging and Engagement: Testing a Tailored Social Belonging Intervention for University Students

Background Prominent theories of motivation suggest that belonging plays a critical role in student success (Connell & Wellborn, 1991). Social-belonging interventions have been shown to improve student belonging, well-being, engagement, and more—especially those from traditionally disadvantaged backgrounds (Walton & Brady, 2017). The current study aimed to explore the effects of a tailored social-belonging intervention delivered in introductory classes at VCU on students’ belonging, engagement, persistence, and achievement. Methods A diverse sample of first-year undergraduate students at VCU participated. To create authentic intervention materials, we collaborated with a diverse group of upper-level undergraduate student researchers who wrote narratives to present vivid stories of how they personally experienced and overcame struggles to belong. Prior to and following the intervention, students completed a survey that assessed student belonging, engagement, and social and academic fit. We also collected student demographics, achievement, and additional data from institutional records. Results Following the implementation of the belonging intervention, data was collected on students’ sense of belonging, their social and academic fit at the university, and other related outcomes. While most students felt as though they belonged at VCU and had the potential to succeed, there were still some students who worried whether they belonged in college. Conclusions From students’ responses, faculty and advisors of first-year students were given an overview on students’ current states of belonging at VCU. As an implication for future research, we argue that including diverse upper-level students as fellow researchers in this work strengthens the authenticity and effectiveness of the belonging intervention.https://scholarscompass.vcu.edu/gradposters/1171/thumbnail.jp

Guide pour la coélaboration de scénarios: Vers la compréhension partagée et l’action commune pour la réforme et la sécurité du foncier forestier

Le Centre de recherche forestière internationale (CIFOR) a lancé en Indonésie, en Ouganda et au Pérou le projet GCS-Tenure, une étude comparative mondiale sur la réforme du foncier forestier. Ce projet a vocation à comparer le régime foncier coutumier et celui qui est inscrit dans la loi, et à étudier l’incidence de leur rapport sur la sécurité foncière des communautés qui dépendent des forêts, notamment des femmes et autres groupes marginalisés. En procédant à des comparaisons à l’échelle mondiale et à l’aide de méthodologies standardisées, cette étude analyse les différences quant à la réussite ou à l’échec des innovations destinées à renforcer la sécurité des droits fonciers, qu’elles soient institutionnelles ou concernent les politiques publiques. Elle permet aussi d’examiner comment ces innovations déterminent les stratégies susceptibles de conduire aux résultats désirés. L’analyse prospective participative (PPA) est une première étape qui permet de mobiliser les principales parties prenantes. Grâce à des réunions participatives, tous les experts définissent et élaborent progressivement un éventail de scénarios de sécurité foncière. Ils conçoivent ensuite les actions correspondant aux scénarios définis. En appliquant la PPA, l’équipe de chercheurs vise à répondre aux questions suivantes : Quels sont les principaux facteurs qui influencent la sécurité du foncier forestier ? Quelles sont les actions possibles pour atténuer les conséquences néfastes (ou aplanir les obstacles qui freinent la mise en œuvre) et favoriser un changement positif (p. ex., un accès équitable pour les femmes et les groupes marginalisés) ? Qui doit être responsable de ces actions ? L’analyse prospective participative est destinée à aider les instances de décision à comprendre les facteurs clés, les difficultés et les conséquences futures des choix stratégiques

Phase separation of signaling molecules promotes T cell receptor signal transduction.

Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling

Phase separation of signaling molecules promotes T cell receptor signal transduction

Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micron- or submicron-sized clusters. However, the functional consequences of such clustering has been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phoshophorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases, and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling