https://www.normalesup.org/~vorgogoz/articles/D.pachea-references/alternative-splicing/Stamm2005-alternative-splicing-review.pdf

Function of alternative splicing.

Dynamin, the founding member of a family of dynamin-like proteins (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live-cell imaging, cell-free studies, X-ray crystallography and genetic studies in mice, has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged, highlighting specific contributions of this GTPase to the physiology of different tissues.

Dynamin, a membrane-remodelling GTPase

As obligatory intracellular parasites, viruses rely on host-cell functions for most aspects of their replication cycle. This is born out during entry, when most viruses that infect vertebrate and insect cells exploit the endocytic activities of the host cell to move into the cytoplasm. Viruses belonging to vaccinia, adeno, picorna and other virus families have been reported to take advantage of macropinocytosis, an endocytic mechanism normally involved in fluid uptake. The virus particles first activate signalling pathways that trigger actin-mediated membrane ruffling and blebbing. Usually, this is followed by the formation of large vacuoles (macropinosomes) at the plasma membrane, internalization of virus particles and penetration by the viruses or their capsids into the cytosol through the limiting membrane of the macropinosomes. We review the molecular machinery involved in macropinocytosis and describe what is known about its role in virus entry.

Virus entry by macropinocytosis

ReviewFunction of alternative splicing

Endocytosis occurs at the cell surface and involves internalization of the plasma membrane (PM) along with its constituent membrane proteins and lipids. Endocytosis is involved in sampling of the extracellular milieu and also serves to regulate various processes initiated at the cell surface. These include nutrient uptake, signaling from cell-surface receptors, and many other processes essential for cell and tissue functioning in metazoans. It is also central to the maintenance of PM lipid and protein homeostasis. There are multiple means of internalization that operate concurrently, at the cell surface. With advancement in high-resolution visualization techniques, it is now possible to track multiple endocytic cargo at the same time, revealing a remarkable diversity of endocytic processes in a single cell. A combination of live cell imaging and efficient genetic manipulations has also aided in understanding the functional hierarchy of molecular players in these mechanisms of internalization. Here we provide an account of various endocytic routes, their mechanisms of operation and occurrence across phyla.

/pdf/endocytosis-unplugged-multiple-ways-to-enter-the-cell-4da1m9g4te.pdf

Endocytosis unplugged: multiple ways to enter the cell

Dynamin (Dyn) is a multifunctional GTPase implicated in several cellular events, including endocytosis, intracellular trafficking, cell signaling, and cytokinesis. The mammalian genome encodes three isoforms, Dyn1, Dyn2, and Dyn3, and several splice variants of each, leading to the suggestion that distinct isoforms and/or distinct splice variants might mediate distinct cellular functions. We generated a conditional Dyn2 KO cell line and performed knockout and reconstitution experiments to explore the isoform- and splice variant specific cellular functions of ubiquitously expressed Dyn2. We find that Dyn2 is required for clathrin-mediated endocytosis (CME), p75 export from the Golgi, and PDGF-stimulated macropinocytosis and cytokinesis, but not for other endocytic pathways. Surprisingly, CME and p75 exocytosis were efficiently rescued by reintroduction of Dyn2, but not Dyn1, suggesting that these two isoforms function differentially in vesicular trafficking in nonneuronal cells. Both isoforms rescued macropinocytosis and cytokinesis, suggesting that dynamin function in these processes might be mechanistically distinct from its role in CME. Although all four Dyn2 splice variants could equally restore CME, Dyn2ba and -bb were more effective at restoring p75 exocytosis. This splice variant specificity correlated with their differential targeting to the Golgi. These studies reveal isoform and splice-variant specific functions for Dyn2.

/pdf/isoform-and-splice-variant-specific-functions-of-dynamin-2-1rd0iz986u.pdf

Isoform and Splice-Variant Specific Functions of Dynamin-2 Revealed by Analysis of Conditional Knock-Out Cells

The invention is directed to heteroaryl compounds useful as inhibitors of various kinase enzymes. In various embodiments, the invention provides a heteroaryl compound having inhibitory bioactivity with respect to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Flt kinase, an Aurora kinase, or a Src kinase, or any combination thereof. Compounds of the invention include bicyclic heteroaryl compounds of formula (I), which can contain a bridging nitrogen atom at a ring junction. The invention further provides methods of synthesis of compounds of the invention, pharmaceutical compositions, pharmaceutical combinations, and methods of treatment of malconditions using compounds of the invention.

Bicyclic heteroaryls as kinase inhibitors

Compounds useful as Rho kinase inhibitors according to formula IA or IB: wherein A, B, D, E, R1, R2 and Ar1 are as defined herein, and any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof, pharmaceutical compositions, methods of treatment, and synthetic methods are provided.

Benzimidazoles and analogs as rho kinase inhibitors

The invention is directed to quinazoline compounds that can inhibit the bioactivity of one or more kinase enzymes, including a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; to methods of use of those compounds; and to methods of preparation of those compounds The inventive compounds can be used in the treatment of malconditions including cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease, viral infection, or myocardial pathology

Quinazoline derivatives as kinase inhibitors

The invention is directed to compounds that can inhibit the bioactivity of one or more kinases such as any of Rho kinases, PKB (Akt) kinases, p70S6K kinase, LIM kinases, or IKK kinases, to methods of use of those compounds, and to methods of preparation of those compounds The inventive compounds can be used In the treatment of a variety of medical malconditions.

Urea and carbamate compounds and analogs as kinase inhibitors

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