Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12

AbstractActivation of the type I TGF β receptor (T β R-I) requires phosphorylation of a regulatory segment known as the GS region, located upstream of the serine/threonine kinase domain in the cytoplasmic portion of the receptor. The crystal structure of a fragment of unphosphorylated T β R-I, containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12. T β R-I adopts an inactive conformation that is maintained by the unphosphorylated GS region. FKBP12 binds to the GS region of the receptor, capping the T β R-II phosphorylation sites and further stabilizing the inactive conformation of T β R-I. Certain structural features at the catalytic center of T β R-I are characteristic of tyrosine kinases rather than Ser/Thr kinases

The transcription factor Rreb1 regulates epithelial architecture, invasiveness, and vasculogenesis in early mouse embryos.

Ras-responsive element-binding protein 1 (Rreb1) is a zinc-finger transcription factor acting downstream of RAS signaling. Rreb1 has been implicated in cancer and Noonan-like RASopathies. However, little is known about its role in mammalian non-disease states. Here, we show that Rreb1 is essential for mouse embryonic development. Loss of Rreb1 led to a reduction in the expression of vasculogenic factors, cardiovascular defects, and embryonic lethality. During gastrulation, the absence of Rreb1 also resulted in the upregulation of cytoskeleton-associated genes, a change in the organization of F-ACTIN and adherens junctions within the pluripotent epiblast, and perturbed epithelial architecture. Moreover, Rreb1 mutant cells ectopically exited the epiblast epithelium through the underlying basement membrane, paralleling cell behaviors observed during metastasis. Thus, disentangling the function of Rreb1 in development should shed light on its role in cancer and other diseases involving loss of epithelial integrity

Interaction of Transforming growth factor-β receptor I with farnesyl-protein transferase-α in yeast and mammalian cells

Transforming growth factor beta (TGF-beta) signals through two transmembrane serine/threonine kinases, known as TbetaR-I and TbetaR-II. Several lines of evidence suggest that TbetaR-II acts as a primary receptor, binding TGF-beta and phosphorylating TbetaR-I whose kinase activity then propagates the signal to unknown substrates. We report an interaction between TbetaR-I and the farnesyl-protein transferase-alpha subunit (FT-alpha) both in a yeast two-hybrid system and in mammalian cells. These findings raise the possibility that TGF-beta might regulate cellular functions by altering the ability of FT-alpha to catalyze isoprenylation of targets such as G proteins, lamins, or cytoskeletal components. However, we provide evidence that TGF-beta action does not alter the overall protein isoprenyl transferase activity in Mv1Lu mink lung epithelial cells. In fact, the beta subunits of farnesyl transferase and geranylgeranyl transferase, which are necessary for the activity of FT-alpha, prevent the association of FT-alpha with TbetaR-I. Furthermore, farnesyl transferase activity is shown to be dispensable for TGF-beta signaling of growth inhibitory and transcriptional responses in these cells. These results suggest that the interaction between TbetaR-I and FT-alpha does not affect the known functions of these two proteins

A hybrid energy storage solution based on supercapacitors and batteries for the grid integration of utility scale photovoltaic plants

This paper presents a 2-level controller managing a hybrid energy storage solution (HESS) for the grid integration of photovoltaic (PV) plants in distribution grids. The HESS is based on the interconnection of a lead-acid battery pack and a supercapacitor pack through a modular power electronics cabinet. The inclusion of the HESS into the PV plant –and not an state-of-the-art energy storage system based on a single technology–, is motivated by the diversity of technical requirements for the provision of the services of grid peak power shaving and PV output power ramp limitation. The 2-level controller ensures a synergistic exploitation of the two storage technologies aiming for an optimal service level of the HESS and minimum battery degradation. The higher level of the controller is based on a mathematical optimization problem that solves with the optimal schedule of the storage technologies for peak power shaving purposes. The power setpoints of this optimization are then complemented by a real time controller managing PV plant output ramp limitation. The HESS performance and associated controller has been proved effective through two case studies. The first one adopts a 6.6 MW PV plant including a HESS solution combining a 5.5 MWh and 2.64 MW lead-acid battery pack with a 0.25 MWh and 1.32 MW supercapacitor pack. The second one reports experimental data from an analogous scenario scaled down to kW level and using a laboratory scale prototype for the HESS. All in all, the hardware and software solutions proposed in this paper contribute to a feasible exploitation of multi-purpose energy storages targeting the needs of renewables' and distribution system operators.Peer ReviewedPostprint (published version

TGFβ Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4

SummaryCells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGFβ in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGFβ via the Smad signaling pathway. TGFβ induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases

Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer.

The mechanisms through which cancer cells lock in altered transcriptional programs in support of metastasis remain largely unknown. Through integrative analysis of clinical breast cancer gene expression datasets, cell line models of breast cancer progression, and mutation data from cancer genome resequencing studies, we identified RNA binding motif protein 47 (RBM47) as a suppressor of breast cancer progression and metastasis. RBM47 inhibited breast cancer re-initiation and growth in experimental models. Transcriptome-wide HITS-CLIP analysis revealed widespread RBM47 binding to mRNAs, most prominently in introns and 3'UTRs. RBM47 altered splicing and abundance of a subset of its target mRNAs. Some of the mRNAs stabilized by RBM47, as exemplified by dickkopf WNT signaling pathway inhibitor 1, inhibit tumor progression downstream of RBM47. Our work identifies RBM47 as an RNA-binding protein that can suppress breast cancer progression and demonstrates how the inactivation of a broadly targeted RNA chaperone enables selection of a pro-metastatic state

Off-target effects dominate a large-scale RNAi screen for modulators of the TGF-β pathway and reveal microRNA regulation of TGFBR2

10.1186/1758-907X-2-3Silence21