Smads Are Structurally Related Intracellular Signaling

The oligonucleotide antisense matches complementary to the region 107–128 of the human Smad7 mRNA sequence, and its

HER2 is an oncogenic growth factor receptor, which belongs in the human epidermal growth factor receptor family. HER2 exists in

Use of Genetic analysis to study the nature of the Smyd1b gene in Cardiac and Skeletal

MMP-9 is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix and have an important role in cancer progression. VEGF is a protein produced by cells that stimulates angiogenesis. It restores the oxygen supply to cells when blood circulation is inadequate and also similar to MMP-9 causes to cancer

Figure 3. Illustration of the protein secondary and tertiary structure of the kinase domain of the LRRK2 protein of a brown rat, consisting of both α-helices and β-sheets, coloured coded from red at the N-terminus to blue at the C-terminus. Shown in ‘sticks’ format is the highly selective, potent

mTOR is also known as FRAP (FKBP12-rapamycin-associated protein), RAFT1 (rapamycin and FKBP12 target), RAPT 1 (rapamycin target 1), or SEP (sirolimus effector protein) that belongs to the PI3K-related protein kinase (PIKKs) family, since its C-terminus shares strong homology to the catalytic domain of PI3K (Figure

The authors found that there was some variability in the expression and the splicing patterns of signaling molecules. From this variability, the authors focus on the Receptor tyrosine kinases (RTKs) because they are an important signaling molecules and is target for possible therapeutics. This variability could be a source for why some therapeutics that target RTKs are unsuccessful.

The canonical Smad pathway involves the Smad proteins of which there are three classes: the R-Smads which are mediated by specific receptors, the common mediator Smads (Co-Smad) and the inhibitory Smads11,15. The Smad2 and 3 proteins are specific to the TGF-β signalling pathway whereas Smad1, 5 and 8 are specific to the BMP-2 signalling pathway15. Within the TGF-β pathway, receptor-regulated Smad2 and Smad3 proteins are phosphorylated by the TGFβRII with both Smads forming complexes with Smad4, a common Smad19. The resulting complex migrates into the nucleus acting as transcription factors for downstream activation of the runt-related transcription factor 2 (Runx2)19. Smad6 and Smad7 are the inhibitory Smads: Smad7 in particular regulates the function of R-Smads by targeting the TGFβRII for degradation and also by binding competitively to Smad4, disrupting Smad2 and 3 binding20.

RAS is a biochemical molecule that is constantly being researched, and new roles and functions are consistently being discovered. The three main subcategories of RAS are K-RAS, N-RAS, and H-RAS. There is also a lesser known variant known as R-RAS. They are all functionally very similar, but function at different general areas within the cell. To discuss the functionality of RAS, it is important to go over the mechanism where it usually functions at the receptor tyrosine kinases (RTKS). RTKS are a specific type of cell-surface receptor, the other major type being G-protein coupled receptors (GPCRs). There are a variety of ligands that can bind, including platelet-derived growth factors, epidermal growth factors, and insulin. The structure of an RTK consists of one hydrophobic

Specific aims: EGFR and c-Met are receptor tyrosine kinases (RTKs), and tyrosine kinase inhibitors (TKIs) against these receptors have been initially effective when prescribed to patients in combination with traditional chemotherapy or radiation. However, the overall efficacy of TKIs is limited due to the development of resistance as seen through clinical trials in NSCLC. Epithelial Mesenchymal Transition (EMT) is a process by which epithelial cells undergo phenotypic and morphological changes to acquire mesenchymal characteristics including increased motility and invasiveness. Currently, the role of EMT in TKI drug resistance is poorly understood. EMT results in loss of tight junction proteins such as E-cadherin and upregulation of transcriptional repressors of these proteins such as ZEB1. Recently, protein arginine methyl transferase 1 (PRMT1) has been shown to be an important regulator of EMT, cancer cell migration and metastasis. However, the role of PRMT1 in TKI resistance is not known. In this study, we propose to evaluate the role of EMT proteins in TKI resistance using H2170 and H358 cell lines (wild type EGFR) that were made resistant to an EGFR inhibitor, erlotinib and a c-Met inhibitor, SU11274 and a combination of both. H3255 cell line (with L858R EGFR mutation), and H1975 cell line with L858R and T790M EGFR mutations which we have made resistant to erlotinib will also be used. Our recent in vitro studies indicate that TKI resistance may be due to the activation

We also assume that the number of initial cell population in a treated condition is the same as one in an untreated control condition. Then cell viability is written as a function of growth rates and time. We consider the same time scale of our cell viability assay in our experiments.Here, we defined tumor and stroma region explicitly based on an image of lung adenocarcinoma patient tissue. Tumor region contains cancer cells. Since not all proteins in cancer cells are directly measurable due to experimental limitation, many players and intermediate proteins in the pathway are not included in our study. For this reason, an interaction between two proteins is not necessarily representing direct interaction. Rather, it represents diverse and abstract influence of one entity to other entity in steady state, where an entity can be a microenvironmental variable, intracellular protein, or cell viability.

Discuss in detail the effects that an activating mutation in the IKBKB gene would be expected to have on the downstream signalling pathway components and target gene expression, and how these effects are measured in the article.

is clearly implicated in the TGF-β1, Notch, Fringe, and selectin functions or signalling [8, 9].

The auto phosphorylation of EGFR by EGF causes the association of Grb2 with the SH2 domain that recruits SOS-1 which is ultimately activating Raf and ERK signalling [30]. Here, ERK kinetics was broadly similar in the three cell lines examined here following stimulation by EGF, it was rapid and transient (Fig. 10F, 11F and 12F), and this could be due to the dynamics of its receptor, as upon EGF activation the EGFR undergoes rapid internalisation and degradation, thereby terminating ERK activation. Hydrolysis of GTP to GDP terminates Ras activation, and although Ras proteins have low GTPase activity, the response was transient. This may be due to negative feedback or other regulatory proteins acting as GTPase-activating proteins being activated by Ras, which in turn accelerates the hydrolysis of GTP to GDP and subsequently prevents prolonged Ras stimulation signalling [31].

Surfactant protein-D (SP-D) is a C-type lectin which is synthesized in various parts of the body. SP-D plays a key role in the auto immune disorders, lung infections and also helpful in the postnatal pregnancy. This also plays an active role in the host-defense mechanisms. In the host defense mechanism SP-D binds with various micro-organisms and other particles that enter the human body and act against them. In our present study we targeted on the interactions of surfactant protein –D with the lipid molecules where their interaction plays an important role in the defense mechanism. In our study lipid molecules were docked against the SP-D protein and interaction studies were carried-out. Mutations were generated at sites F335G and R343V and interactions of the lipids with the mutated protein molecules were studied. Among the wild and the mutant protein molecules, mutant protein F335G showed highest interaction with the lipid molecule distearoylphosphatidylcholine with cDocker energy of 94.726. These studied showed that mutant molecules are showing highest binding with the lipid molecules when compared to the wild protein molecule. Among all ligand molecules chosen, distearoylphosphatidylcholine showed highest interaction followed by dilaurylphosphatidylcholine, dipalmitoylphosphatidylcholine with tocopherol showing the least binding affinity with both wild and the mutant protein molecules.