HER4/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.

Growth factors, insulin signaling, and nutrients are important regulators of ␤-cell mass and function. The events linking these signals to the regulation of ␤-cell mass are not completely understood. The mTOR pathway integrates signals from growth factors and nutrients. Here, we evaluated the role of the mTOR/ raptor (mTORC1) signaling in proliferative conditions induced by controlled activation of Akt signaling. These experiments show that the mTORC1 is a major regulator of ␤-cell cycle progression by modulation of cyclin D2, D3, and Cdk4 activity. The regulation of cell cycle progression by mTORC1 signaling resulted from modulation of the synthesis and stability of cyclin D2, a critical regulator of ␤-cell cycle, proliferation, and mass. These studies provide novel insights into the regulation of cell cycle by the mTORC1, provide a mechanism for the antiproliferative effects of rapamycin, and imply that the use of rapamycin could negatively impact the success of islet transplantation and the adaptation of ␤-cells to insulin resistance.The defects that result in diabetes are diverse, but the loss of pancreatic ␤-cell mass is a critical determinant for the development of this disease (1, 2). The capacity for ␤-cells to expand in response to insulin resistance is required to maintain glucose homeostasis and prevent type 2 diabetes. Pancreatic ␤-cell mass is regulated by a dynamic balance of neogenesis, proliferation, hypertrophy, and apoptosis (3). In particular, ␤-cell proliferation (determined by the number of mature ␤-cells entering the cell cycle) has a major role in the maintenance of ␤-cell mass in adult life and after proliferative stimuli (4). Although there has been much research showing the role of ␤-cell mass in diabetes, there is a lack of knowledge pertaining to how ␤-cells enter the cell cycle, proliferate, and increase mass.In pancreatic ␤-cells, glucose, amino acids, and growth factors have been shown to induce G 1 -S progression (5-7). Recent studies have demonstrated that mTOR integrates growth factors and nutrient signals and is essential for cell growth and proliferation (8). One of the major mechanisms by which nutrient and growth factors regulate mTOR activity involves the tuberous sclerosis complex 2 (TSC2) 2 gene product (tuberin) as well as TSC1 (hamartin) and the small G protein Ras homolog enriched in brain. Phosphorylation of TSC2 by the serine-threonine kinase AKT induces mTOR signaling by derepressing the TSC2 GTPase-activating protein activity toward Ras homolog enriched in brain, (9 -13). Recent findings indicate that mTOR is a part of two distinct complexes: mTORC1 and mTORC2 (14,15). The mammalian mTORC1 contains Raptor and the G protein ␤-subunit-like protein (G␤L). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K), eukaryote initiation factor 4E-binding protein 1, and eukaryote initiation factor 4E (16). The mTORC2 complex includes mTOR and rictor and is insensitive to rapamycin (14, 15). This complex is potentially important for the regulation o...

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Sex Comb on Midleg (SCM) belongs to the Polycomb group of proteins, which are involved in transcriptional regulation in Drosophila. It is one of the components of Polycomb repressive complex 1, a multiprotein complex of Polycomb group proteins involved in the maintenance of repression and the blocking of chromatin remodeling. SCM contains two ϳ100-residue malignant brain tumor (MBT) repeats at the N terminus. These repeats are also found in other proteins involved in transcriptional repression. Here, we report the 1.78-Å crystal structure of the two MBT repeats of SCM-like 2 (SCML2), a human homologue of SCM. Each repeat consists of an extended arm and a ␤-barrel core. There are significant structural similarities to the Tudor, PWWP, and chromo domains, suggesting probable evolutionary relationships and functional similarities between the MBT repeats and these domains.