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Angela Glading, Ph.D.

Angela Glading, Ph.D.

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About Me

Faculty Appointments

Associate Professor - Department of Pharmacology and Physiology (SMD)

Credentials

Post-doctoral Training & Residency

Department of Medicine, University of California San Diego, Supervisor: Mark H. Ginsberg 2004 - 2008

Department of Cell Biology, The Scripps Research Institute, Supervisor: Mark H. Ginsberg 2002 - 2004

Education

Ph.D. | University of Pittsburgh. Cellular and Molecular Pathology. 2002

BS | Whitworth College. Biochemistry and Biology. 1997

Awards

The Takashi Murachi Young Investigator Award. 2001

Research

In order for normal cells to function, they must adhere to their immediate environment, which includes other cells and proteins. In return, cells receive both mechanical and chemical signals from their environment that are important for cellular processes such as migration, proliferation, and gene e...
In order for normal cells to function, they must adhere to their immediate environment, which includes other cells and proteins. In return, cells receive both mechanical and chemical signals from their environment that are important for cellular processes such as migration, proliferation, and gene expression. Defective or improperly regulated adhesion is observed in a wide variety of human diseases, including the major killers cancer and cardiovascular disease.

Research in the Glading lab focuses on unraveling how cell adhesion signaling regulates cellular behavior.

Currently, our work concentrates on how cell-cell adhesion modulates cell growth and differentiation in both the normal and disease state. Our main experimental context is the endothelial cell and the intact blood vessel. Vessel function is reliant on the ability of vessels to maintain an effective barrier between the blood and tissue, which is primarily regulated at the level of the endothelial cell-cell contact (endothelial junctions). Changes in this barrier regulate the normal immune response and contribute to the growth of new vessels (angiogenesis).

Recently, we described KRIT1 as a scaffolding protein that nucleates a signaling complex at sites of endothelial cell-cell contact. In confluent endothelial cells, the KRIT1 complex associates with cell-cell contacts and is required for junctional stability downstream of active Rap1 (Glading et al 2007). KRIT1 also sits at the nexus of multiple signaling pathways, including the canonical beta-catenin pathway (Glading and Ginsberg, 2010), vascular-endothelial growth factor receptor (VEGFR) activation (DiStefano and Glading, in press), RhoA/Rho Kinase activity (Glading et al, 2007), and Notch signaling, which KRIT1 supports or modifies to promote a stable vascular barrier. Our ongoing research aims to understand cell-cell contact impacts global cell signaling by examining how KRIT1 signaling contributes to changes in cellular behavior.

We use KRIT1 deficient endothelial cells (siRNA, CRISPR) and tissues (KRIT1 knockout and KRIT1 endothelial-specific knockout mice) as models to probe the consequence of loss of endothelial cell-cell contact on endothelial behavior and vessel integrity in vitro and in vivo. By using genetic manipulation of KRIT1, we have been able to prove that loss of cell-cell contact stimulates broad changes in gene expression (Glading, 2010), induces vascular permeability in vivo (Corr et al, 2012), and promotes angiogenesis (unpublished data), as just a few examples. By combining molecular and biochemical examination of specific signaling mechanisms with real-time physiology, we are able to establish key signaling events as critical for normal vascular function. In current research, we are using this approach to explore the crosstalk between inflammatory signaling, angiogenesis and cell-cell contact in the relevant physiological contexts of vascular integrity and cancer.

Publications

Journal Articles

KRIT1 in vascular biology and beyond.

Glading A

Bioscience reports.. 2024 July 3144 (7)Epub 1900 01 01.

KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease.

Perrelli A, Ferraris C, Berni E, Glading AJ, Retta SF

Antioxidants & redox signaling.. 2023 March 38 (7-9):496-528. Epub 11/01/2022.

KRIT1-mediated regulation of neutrophil adhesion and motility.

Nobiletti N, Liu J, Glading AJ

The FEBS journal.. 2023 February 290 (4):1078-1095. Epub 09/20/2022.

Contribution of protein-protein interactions to the endothelial-barrier-stabilizing function of KRIT1.

Swamy H, Glading AJ

Journal of cell science.. 2022 January 15135 (2)Epub 01/25/2022.

Is Location Everything? Regulation of the Endothelial CCM Signaling Complex.

Swamy H, Glading AJ

Frontiers in cardiovascular medicine.. 2022 9 :954780. Epub 07/11/2022.

Protein kinase C? regulates the nucleocytoplasmic shuttling of KRIT1.

De Luca E, Perrelli A, Swamy H, Nitti M, Passalacqua M, Furfaro AL, Salzano AM, Scaloni A, Glading AJ, Retta SF

Journal of cell science.. 2021 February 4134 (3)Epub 02/04/2021.

Microvascular Mimetics for the Study of Leukocyte-Endothelial Interactions.

Khire TS, Salminen AT, Swamy H, Lucas KS, McCloskey MC, Ajalik RE, Chung HH, Gaborski TR, Waugh RE, Glading AJ, McGrath JL

Cellular and molecular bioengineering.. 2020 April 13 (2):125-139. Epub 01/31/2020.

Protein kinase C? (PKC?) regulates the nucleocytoplasmic shuttling of KRIT1.

De Luca E, Perrelli A, Swamy H, Nitti M, Passalacqua M, Furfaro AL, Salzano AM, Scaloni A, Glading AJ, Retta SF

Journal of cell science.. 2020 January 1 Epub 01/01/2020.

VEGF signalling enhances lesion burden in KRIT1 deficient mice.

DiStefano PV, Glading AJ

Journal of cellular and molecular medicine.. 2020 January 24 (1):632-639. Epub 11/20/2019.

Isolation of Cerebral Endothelial Cells from CCM1/KRIT1 Null Mouse Brain.

Nobiletti N, Glading AJ

Methods in molecular biology.. 2020 2152 :259-265. Epub 1900 01 01.

Measurement of Endothelial Barrier Function in Mouse Models of Cerebral Cavernous Malformations Using Intravital Microscopy.

Glading AJ

Methods in molecular biology.. 2020 2152 :387-400. Epub 1900 01 01.

Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium.

Goitre L, DiStefano PV, Moglia A, Nobiletti N, Baldini E, Trabalzini L, Keubel J, Trapani E, Shuvaev VV, Muzykantov VR, Sarelius IH, Retta SF, Glading AJ

Scientific reports.. 2017 August 157 (1):8296. Epub 08/15/2017.

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin.

Retta SF, Glading AJ

The international journal of biochemistry & cell biology.. 2016 December 81 (Pt B):254-270. Epub 09/14/2016.

Phospholipase C? Modulates Rap1 Activity and the Endothelial Barrier.

DiStefano PV, Smrcka AV, Glading AJ

PloS one.. 2016 11 (9):e0162338. Epub 09/09/2016.

Control of vascular permeability by adhesion molecules.

Sarelius IH, Glading AJ

Tissue barriers.. 2015 3 (1-2):e985954. Epub 04/03/2015.

KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling.

Distefano PV, Kuebel JM, Sarelius IH, Glading AJ

The Journal of biological chemistry.. 2014 November 21289 (47):33054-65. Epub 10/15/2014.

Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo.

Corr M, Lerman I, Keubel JM, Ronacher L, Misra R, Lund F, Sarelius IH, Glading AJ

Arteriosclerosis, thrombosis, and vascular biology.. 2012 November 32 (11):2702-10. Epub 08/23/2012.

Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling.

Glading AJ, Ginsberg MH

Disease models & mechanisms.. 2010 3 (1-2):73-83. Epub 12/09/2009.

KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions.

Glading A, Han J, Stockton RA, Ginsberg MH

The Journal of cell biology.. 2007 October 22179 (2):247-54. Epub 1900 01 01.

PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2.

Glading A, Koziol JA, Krueger J, Ginsberg MH

Cancer research.. 2007 February 1567 (4):1536-44. Epub 1900 01 01.

Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation.

Krueger J, Chou FL, Glading A, Schaefer E, Ginsberg MH

Molecular biology of the cell.. 2005 August 16 (8):3552-61. Epub 05/25/2005.

Interferon-inducible protein 9 (CXCL11)-induced cell motility in keratinocytes requires calcium flux-dependent activation of mu-calpain.

Satish L, Blair HC, Glading A, Wells A

Molecular and cellular biology.. 2005 March 25 (5):1922-41. Epub 1900 01 01.

Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.

Glading A, Bodnar RJ, Reynolds IJ, Shiraha H, Satish L, Potter DA, Blair HC, Wells A

Molecular and cellular biology.. 2004 March 24 (6):2499-512. Epub 1900 01 01.

PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation.

Chou FL, Hill JM, Hsieh JC, Pouyssegur J, Brunet A, Glading A, Uberall F, Ramos JW, Werner MH, Ginsberg MH

The Journal of biological chemistry.. 2003 December 26278 (52):52587-97. Epub 09/23/2003.

Activation of m-calpain (calpain II) by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain.

Shiraha H, Glading A, Chou J, Jia Z, Wells A

Molecular and cellular biology.. 2002 April 22 (8):2716-27. Epub 1900 01 01.

Cutting to the chase: calpain proteases in cell motility.

Glading A, Lauffenburger DA, Wells A

Trends in cell biology.. 2002 January 12 (1):46-54. Epub 1900 01 01.

Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling.

Glading A, Uberall F, Keyse SM, Lauffenburger DA, Wells A

The Journal of biological chemistry.. 2001 June 29276 (26):23341-8. Epub 04/23/2001.

Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway.

Glading A, Chang P, Lauffenburger DA, Wells A

The Journal of biological chemistry.. 2000 January 28275 (4):2390-8. Epub 1900 01 01.

IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity.

Shiraha H, Glading A, Gupta K, Wells A

The Journal of cell biology.. 1999 July 12146 (1):243-54. Epub 1900 01 01.

Epidermal growth factor receptor-mediated motility in fibroblasts.

Wells A, Gupta K, Chang P, Swindle S, Glading A, Shiraha H

Microscopy research and technique.. 1998 December 143 (5):395-411. Epub 1900 01 01.