A5025707259- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Cellular Mechanics and Interactions
- Lipid Membrane Structure and Behavior
- Alzheimer's disease research and treatments
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Multiple Myeloma Research and Treatments
- Cancer Treatment and Pharmacology
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Axon Guidance and Neuronal Signaling
- Endoplasmic Reticulum Stress and Disease
- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Photoreceptor and optogenetics research
- 14-3-3 protein interactions
- Nerve injury and regeneration
- Nuclear Structure and Function
- Immune cells in cancer
- HER2/EGFR in Cancer Research
- Retinal Development and Disorders
- Cardiomyopathy and Myosin Studies
Columbia University
2014-2025
Columbia University Irving Medical Center
2002-2025
Columbia College
2023
Royal College of Physicians
2023
Ospedale Garibaldi
2015-2023
New York Proton Center
2022
New York University
2002-2005
University of Chicago
1999
A critical microtubule (MT) polarization event in cell migration is the Rho/mDia-dependent stabilization of a subset MTs oriented toward direction migration. Although mDia nucleates actin filaments, it unclear whether this or separate activity underlies MT stabilization. We generated two mutants (K853A and I704A) constitutively active version mDia2 containing formin homology domains 1 2 (FH1FH2) found that they still induced stable bound to TIP proteins EB1 APC, which have also been...
The tumor suppressor protein adenomatous polyposis coli (APC) regulates cell protrusion and migration, processes that require the coordinated regulation of actin microtubule dynamics. APC localizes in vivo to plus ends actin-rich cortical protrusions, has well-documented direct effects on However, its potential dynamics have remained elusive. Here, we show C-terminal âbasicâ domain (APC-B) potently nucleates formation filaments vitro stimulates assembly cells. Nucleation is achieved by a...
Small molecule inhibitors are prime reagents for studies in microtubule cytoskeleton research, being applicable across a range of biological models and not requiring genetic engineering. However, traditional chemical cannot be experimentally applied with spatiotemporal precision suiting the length time scales inherent to microtubule-dependent cellular processes. We have synthesised photoswitchable paclitaxel-based stabilisers, whose binding is induced by photoisomerisation their metastable...
Microglia reactivity entails a large-scale remodeling of cellular geometry, but the behavior microtubule cytoskeleton during these changes remains unexplored. Here we show that activated microglia provide an example reorganization from non-centrosomal array parallel and stable microtubules to radial more dynamic microtubules. While in homeostatic state, nucleate at Golgi outposts, activating signaling induces recruitment nucleating material nearby centrosome, process inhibited by...
Adenomatous polyposis coli (APC) protein is a large tumor suppressor that truncated in most colorectal cancers. The carboxyl-terminal third of APC mediates direct interactions with microtubules and the microtubule plus-end tracking EB1. In addition, has been localized to actin-rich regions cells, but mechanism functional significance this localization have remained unclear. Here we show purified basic domain human (APC-basic) bound directly bundled actin filaments associated stress fibers...
T cell antigen receptorâproximal signaling components, Rho-family GTPases, and formin proteins DIA1 FMNL1 have been implicated in centrosome reorientation to the immunological synapse of lymphocytes. However, role these molecules process is not yet defined. Here we find that a subset microtubules became rapidly stabilized their α-tubulin subunit posttranslationally detyrosinated after engagement receptor. Formation stabilized, required INF2, which was also found be essential for...
Ribosome-associated vesicles are a novel, dynamic ER-derived organelle.
Mutations in the X-linked retinitis pigmentosa 2 gene cause progressive degeneration of photoreceptor cells. The protein (RP2) is similar sequence to tubulin-specific chaperone cofactor C. Together with cofactors D and E, C stimulates GTPase activity native tubulin, a reaction regulated by ADP-ribosylation factor-like protein. Here we show that presence D, RP2 also tubulin. We find this function abolished mutation an arginine residue conserved both RP2. Notably, mutations alter codon...
Abstract Naturally occurring antimutagenic compounds are extensively analyzed for their capacity to protect cells from induced damage. We selected two agents, taurine and ellagic acid, treated in the literature as antioxidants, but whose activity is insufficiently known. This paper reports on ability of these agents act against damage by mitomycinâC hydrogen peroxide Chinese hamster ovary cultivated vitro. Cytogenetic cytofluorimetric analyses were performed. Ellagic acid proved have more...
In migrating fibroblasts, RhoA and its effector mDia1 regulate the selective stabilization of microtubules (MTs) polarized in direction migration. The conserved formin homology 2 domain is involved both actin polymerization MT stabilization, relationship between these two activities unknown. We found that latrunculin A (LatA) jasplakinolide, drugs release from filament barbed ends, stimulated stable formation serum-starved fibroblasts caused a redistribution onto MTs. Knockdown by small...
Oligomeric Amyloid ÎČ1â42 (AÎČ) plays a crucial synaptotoxic role in Alzheimerâs disease, and hyperphosphorylated tau facilitates AÎČ toxicity. The link between tau, however, remains controversial. In this study, we find that hippocampal neurons, acutely induces tubulin posttranslational modifications (PTMs) stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities corrects synaptotoxicity...
Multiple formins regulate microtubule (MT) arrays, but whether they function individually or in a common pathway is unknown. Lysophosphatidic acid (LPA) stimulates the formation of stabilized detyrosinated MTs (Glu MTs) NIH3T3 fibroblasts through RhoA and formin mDia1. Here we show that another formin, INF2, necessary for mDia1-mediated induction Glu regulation MT dynamics mDia1 can be bypassed by activating INF2. INF2 localized to after LPA treatment an mDia1-dependent manner, suggesting...
After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator actin microtubules (MTs), powering regeneration. In cones, Pfn1 increased retrograde flow, MT speed, invasion filopodia MTs,...
Abstract Microtubules play fundamental roles in the maintenance of neuronal processes and synaptic function plasticity. While dynamic microtubules are mainly composed tyrosinated tubulin, long-lived contain detyrosinated suggesting that tubulin tyrosination/detyrosination cycle is a key player microtubule dynamics homeostasis, conditions go awry neurodegenerative diseases. In cycle, C-terminal tyrosine α-tubulin removed by carboxypeptidases re-added ligase (TTL). Here we show TTL...
Significance Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating âdying backâ featuring distal-to-proximal nerve degeneration seen in cancer patients undergoing chemotherapy. The pathogenenic mechanisms of CIPN are largely unknown. We report that sensory neurons, the CIPN-inducing drug bortezomib caused axonopathy and disrupted mitochondria motility by increasing delta 2 tubulin (D2), only irreversible posttranslational modification marker hyper-stable microtubules. These...
Abstract Two families of GTPases, Arfs and Ypt/rabs, are key regulators vesicular transport. While Arf proteins implicated in vesicle budding from the donor compartment, Ypt/rab involved targeting vesicles to acceptor compartment. Recently, we have shown a role for Ypt31/32p exit yeast trans-Golgi, suggesting possible function as well. Here report identification new member Sec7-domain family, SYT1, high-copy suppressor ypt31/32 mutation. Several that belong including Gea1p, recently been...
Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification RNA-modifying enzymes has opened the possibility investigating role epitranscriptomic changes play in disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one few known brain-enriched methyltransferases able methylate mammalian non-coding RNAs. NSun2 loss due autosomal-recessive mutations been associated with neurological abnormalities...
Advances in cancer treatment have led to a steady increase the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means prevention or direct available. Herein, we present Carba1, novel bi-functional carbazole that mitigates through two distinct mechanisms. First, by interacting tubulin, Carba1 reduces required dose taxanes, widely used chemotherapy drugs...