Biosketch / Results /

John S. Munger, M.D.

Associate Professor; Co-Director Honors Program
Departments of Medicine (Pulmy&CCM Div) and Cell Biology (Cell Biology)

Clinical Addresses

550 FIRST AVENUE
NEW YORK, NY 10016
Phone: 212-263-5745

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Medical Specialties

Pulmonary Medicine

Clinical Responsibilities

As a member of the Division of Pulmonary and Critical Care Medicine, I attend in the Medical Intensive Care Unit of Bellevue Hospital Center approximately eight weeks per year. Also, I provide weekend coverage for the Special Care Unit at the Hospital for Joint Diseases, an NYU-affiliated hospital located in Manhattan.

Attending physician, Bellevue Hospital Center, Pulmonary and Critical Care Medicine

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Board Certification

1985 — Ab Internal Medicine - Internal Medicine
1990 — Ab Internal Medicine (Pulmonary Disease)
1991 — Ab Internal Medicine (Critical Care Medicine)

Education

1982 — Washington University, Medical Education
1982-1985 — Emory University Hospital (Internal Medicine), Internship
1982-1985 — Emory University Hospital (Internal Medicine), Residency Training
1988-1991 — Brigham & Womens Hospital (Pulmonary, Crit Care), Clinical Fellowships

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Research Summary

Our lab studies how latent forms of TGFβ are activated by integrins in vivo.

TGFβ is a ubiquitously produced growth factor with important roles in pathologic processes such as cancer, fibrosis and autoimmunity, and in normal development, wound repair and homeostasis. There are three TGFβ isoforms, and all are secreted in a latent form. Latency is the result of a noncovalent association of the growth factor with its propeptide, which is called latency-associate peptide (LAP). TGFβ must be released from LAP before it can bind TGFβ receptors. The activation step is highly regulated but the specific activation mechanisms involved vivo have been poorly understood.

We discovered that αvβ6, a cell surface adhesion molecule in the integrin family, can activate latent TGFβ1 and TGFβ3 by interacting with an RGD sequence in the TGFβ1 and TGFβ3 LAPs. αvβ6 is expressed in epithelia, particularly after injury. Mice lacking αvβ6 have lung inflammation and are protected from lung fibrosis due to a relative lack of TGFβ signaling in the lung.

We also collaborated with S. Nishimura's lab at UCSF to show that a second RGD-binding integrin, αvβ8, activates TGFβ1 and TGFβ3. Mice lacking this integrin have abnormalities in vascular development. Comparison of knockouts of the two TGFβs and the two β integrin subunits reveals several partially or completely overlapping abnormalities in palate closure, immune regulation, and vascular development, suggesting that αvβ6 and αvβ8 are key TGFβ1/3 activators in vivo.

To determine the role of all RGD-binding integrins in the activation of latent TGFβ1, we made mice with a knock-in mutation of the TGFβ1 gene that changes the RGD site to RGE. These mice produce normal amounts of latent TGFβ1, but it cannot be activated by RGD-binding integrins. Strikingly, the mice have the same abnormalities seen in TGFβ1-null mice, indicating that RGD-binding integrins are indispensable for TGFβ1 activation.

We are currently further exploring the connection between these two integrins and the two RGD-containing TGFβ isoforms by generating mice with combined TGFβ1/3 mutations and mice with combined αvβ6/αvβ8 deficits. Our results support a tight functional system involving the two TGFβs and the two activating integrins. For example, mice with combined αvβ6/αvβ8 deficits have completely penetrant cleft palate, and mice with combined TGFβ1/3 mutations have the CNS vascular changes seen in αvβ8-null mice.

We are now focusing on the immune phenotype of mice lacking function of both αvβ6 and αvβ8. These mice develop severe autoimmune reactions that appear identical to (if not more severe than) those of TGFβ1-null mice. Also, we are testing the effectiveness of an inhibitory anti-αvβ6 mAb, developed by Biogen Idec, in mouse models of lung fibrosis. We find that anti-αvβ6 treatment effectively prevents radiation-induced lung fibrosis in mice, raising the possibility that such treatment might benefit patients with various forms of lung fibrosis.

Research Interests

How integrins activate latent TGFβ1 and TGFβ3 during development and in disease.

Research Keywords

Transforming growth factor-beta (TGF-beta), fibrosis, prostate cancer, dendritic cells, wounds, wound healing, radiation

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All data from NYU Health Sciences Library Faculty Bibliography — -

Contact:
http://hsl.med.nyu.edu/faculty-bibliography-search

Sonic Hedgehog Signaling in the Lung - from Development to Disease
Kugler, Matthias C; Joyner, Alexandra L; Loomis, Cynthia A; Munger, John S
2014 Jul;:339e-341e, American journal of respiratory cell & molecular biology
— id: 1089832, year: 2014, vol: , page: 339e, stat: Journal Article,

Hedgehog Signaling in Neonatal and Adult Lung
Liu, Li; Kugler, Matthias C; Loomis, Cynthia A; Samdani, Rashmi; Zhao, Zhicheng; Chen, Gregory J; Brandt, Julia P; Brownell, Isaac; Joyner, Alexandra L; Rom, William N; Munger, John S
2013 Feb;:703-710 e59461, American journal of respiratory cell & molecular biology
— id: 353072, year: 2013, vol: , page: 703, stat: Journal Article,

Cross Talk among TGF-beta Signaling Pathways, Integrins, and the Extracellular Matrix
Munger, John S; Sheppard, Dean
2011 Nov;3(11):a005017-a005017, Cold Spring Harbor perspectives in biology
— id: 141722, year: 2011, vol: 3, page: a005017, stat: Journal Article,

Depletion of T Cells Potentiates Radiation-induced Acute Pneumonitis
Cheng, S. K.; Formenti, S.; Munger, J.
2010 OCT 13 ;78(3):S37-S38, International journal of radiation oncology biology physics
— id: 114014, year: 2010, vol: 78, page: S37, stat: Journal Article,

Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice
Aluwihare, Poshala; Mu, Zhenyu; Zhao, Zhicheng; Yu, Dawen; Weinreb, Paul H; Horan, Gerald S; Violette, Shelia M; Munger, John S
2009 Jan 15;122(Pt 2):227-232, Journal of cell science
— id: 95543, year: 2009, vol: 122, page: 227, stat: Journal Article,

Inhibition of Integrin beta 6 Prevents Radiation-induced Apoptosis of Intestinal Crypt Cells
Cheng, SK; Horan, GS; Weinreb, PH; Violette, SM; Formenti, SC; Munger, JS
2009 NOV ;75(3):S169-S170, International journal of radiation oncology biology physics
— id: 106170, year: 2009, vol: 75, page: S169, stat: Journal Article,

Anti-integrin beta 6 Therapy Reverses Radiation-induced Lung Fibrosis
Munger, J; Cheng, SK; Horan, GS; Weinreb, PH; Violette, SM; Formenti, SC
2009 NOV ;75(3):S173-S173, International journal of radiation oncology biology physics
— id: 106171, year: 2009, vol: 75, page: S173, stat: Journal Article,

What the lung has taught us about latent TGF-beta activation
Aluwihare, Poshala; Munger, John S
2008 Nov;39(5):499-502, American journal of respiratory cell & molecular biology
— id: 93380, year: 2008, vol: 39, page: 499, stat: Journal Article,

TGFbeta1 and TGFbeta3 are partially redundant effectors in brain vascular morphogenesis
Mu, Zhenyu; Yang, Zhiwei; Yu, Dawen; Zhao, Zhicheng; Munger, John S
2008 May-Jun;125(5-6):508-516, Mechanisms of development
— id: 81571, year: 2008, vol: 125, page: 508, stat: Journal Article,

Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis
Puthawala, Khalid; Hadjiangelis, Nicos; Jacoby, Steven C; Bayongan, Emmanuel; Zhao, Zhicheng; Yang, Zhiwei; Devitt, Mary Louise; Horan, Gerald S; Weinreb, Paul H; Lukashev, Matvey E; Violette, Shelia M; Grant, Kristen S; Colarossi, Cristina; Formenti, Silvia C; Munger, John S
2008 Jan 1;177(1):82-90, American journal of respiratory & critical care medicine
— id: 75454, year: 2008, vol: 177, page: 82, stat: Journal Article,

The integrin-TGF beta axis: Inhibition of integrin alpha v beta 6 prevents radiation-induced lung fibrosis
Munger, J; Cheng, SK; Puthawala, K; Hadjiangelis, N; Jacoby, S; Formenti, SC
2007 JAN ;69(3):S1-S1, International journal of radiation oncology biology physics
— id: 87190, year: 2007, vol: 69, page: S1, stat: Journal Article,

Absence of integrin-mediated TGF{beta}1 activation in vivo recapitulates the phenotype of TGF{beta}1-null mice
Yang, Zhiwei; Mu, Zhenyu; Dabovic, Branka; Jurukovski, Vladimir; Yu, Dawen; Sung, Joanne; Xiong, Xiaozhong; Munger, John S
2007 Mar 12;176(6):787-793, Journal of cell biology
— id: 71138, year: 2007, vol: 176, page: 787, stat: Journal Article,

Inhibition of TGF-beta activation by integrin-beta6 is protective against acute radiation skin injury
Cheng, S; Jacoby, S; Grant, K; Xavier, S; Munger, J; Formenti, S
2005 NOV 16 ;63(2):S461-S462, International journal of radiation oncology biology physics
— id: 58996, year: 2005, vol: 63, page: S461, stat: Journal Article,

Antibody to avb6 integrin prevents radiation-induced lung fibrosis
Formenti, SC; Jacoby, S; Grant, K; Horan, G; Weinreb; Devitt, M; Munger, J
2005 ;63(2):2408-2408, International journal of radiation oncology biology physics
— id: 109266, year: 2005, vol: 63, page: 2408, stat: Journal Article,

Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1
Annes, Justin P; Chen, Yan; Munger, John S; Rifkin, Daniel B
2004 Jun 7;165(5):723-734, Journal of cell biology
— id: 44942, year: 2004, vol: 165, page: 723, stat: Journal Article,

A genetic screen to identify latent transforming growth factor beta activators
Annes, Justin; Vassallo, Melinda; Munger, John S; Rifkin, Daniel B
2004 Apr 1;327(1):45-54, Analytical biochemistry
— id: 42347, year: 2004, vol: 327, page: 45, stat: Journal Article,

The integrin alpha v beta 6-knockout mouse is protected from radiation-induced lung fibrosis: Implications for the clinic
Munger, J; Hadjiangelis, N; Emmanuel, B; Devitt, M; Formenti, SC
2004 ;60(1):S327-S327 #1120, International journal of radiation oncology biology physics
— id: 109271, year: 2004, vol: 60, page: S327, stat: Journal Article,

Langerhans cell differentiation is dependent on integrin-mediated activation of TGF-beta 1
Sung, JJ; Habib, JZ; Munger, JS
2004 MAR ;122(3):A103-A103, Journal of investigative dermatology
— id: 46579, year: 2004, vol: 122, page: A103, stat: Journal Article,

Making sense of latent TGFbeta activation
Annes, Justin P; Munger, John S; Rifkin, Daniel B
2003 Jan 15;116(Pt 2):217-224, Journal of cell science
— id: 35175, year: 2003, vol: 116, page: 217, stat: Journal Article,

The integrin alphaVbeta6 binds and activates latent TGFbeta3
Annes, Justin P; Rifkin, Daniel B; Munger, John S
2002 Jan 30;511(1-3):65-68, FEBS letters
— id: 28180, year: 2002, vol: 511, page: 65, stat: Journal Article,

Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1
Lu, Min; Munger, John S; Steadele, Melissa; Busald, Christina; Tellier, Marinka; Schnapp, Lynn M
2002 Dec 1;115(Pt 23):4641-4648, Journal of cell science
— id: 35176, year: 2002, vol: 115, page: 4641, stat: Journal Article,

The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1
Mu, Dezhi; Cambier, Stephanie; Fjellbirkeland, Lars; Baron, Jody L; Munger, John S; Kawakatsu, Hisaaki; Sheppard, Dean; Broaddus, V Courtney; Nishimura, Stephen L
2002 Apr 29;157(3):493-507, Journal of cell biology
— id: 28181, year: 2002, vol: 157, page: 493, stat: Journal Article,

Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition
Parekh, Trilok V; Gama, Patricia; Wen, Xie; Demopoulos, Rita; Munger, John S; Carcangiu, Maria-Luisa; Reiss, Michael; Gold, Leslie I
2002 May 15;62(10):2778-2790, Cancer research
— id: 32907, year: 2002, vol: 62, page: 2778, stat: Journal Article,

Measurement of active TGF-beta generated by cultured cells
Mazzieri R; Munger JS; Rifkin DB
2000 ;142:13-27, Methods in molecular biology
— id: 11706, year: 2000, vol: 142, page: 13, stat: Journal Article,

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis
Munger JS; Huang X; Kawakatsu H; Griffiths MJ; Dalton SL; Wu J; Pittet JF; Kaminski N; Garat C; Matthay MA; Rifkin DB; Sheppard D
1999 Feb 5;96(3):319-328, Cell
— id: 7411, year: 1999, vol: 96, page: 319, stat: Journal Article,

Proteolytic control of growth factor availability
Rifkin DB; Mazzieri R; Munger JS; Noguera I; Sung J
1999 Jan;107(1):80-85, Apmis
— id: 6074, year: 1999, vol: 107, page: 80, stat: Journal Article,

Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1
Munger JS; Harpel JG; Giancotti FG; Rifkin DB
1998 Sep;9(9):2627-2638, Molecular biology of the cell
— id: 12078, year: 1998, vol: 9, page: 2627, stat: Journal Article,

TGF-beta latency: biological significance and mechanisms of activation
Gleizes PE; Munger JS; Nunes I; Harpel JG; Mazzieri R; Noguera I; Rifkin DB
1997 ;15(3):190-197, Stem cells
— id: 7154, year: 1997, vol: 15, page: 190, stat: Journal Article,

Latent transforming growth factor-beta: structural features and mechanisms of activation
Munger JS; Harpel JG; Gleizes PE; Mazzieri R; Nunes I; Rifkin DB
1997 May;51(5):1376-1382, Kidney international
— id: 35177, year: 1997, vol: 51, page: 1376, stat: Journal Article,

Plasminogen/plasminogen activator and growth factor activation
Rifkin DB; Gleizes PE; Harpel J; Nunes I; Munger J; Mazzieri R; Noguera I
1997 ;212:105-15; discussion 116, CIBA Foundation symposium
— id: 12147, year: 1997, vol: 212, page: 105, stat: Journal Article,

Tissue destruction by proteases
Munger, John S; Chapman, Harold A
Tuberculosis Boston : Little Brown, 1996,
— id: 4835, year: 1996, vol: , page: ?, stat: Chapter,

Structure and activation of the large latent transforming growth factor-beta complex
Nunes I; Munger JS; Harpel JG; Nagano Y; Shapiro RL; Gleizes PE; Rifkin DB
1996 Mar;20 Suppl 3:S4-S8, International journal of obesity & related metabolic disorders
— id: 12639, year: 1996, vol: 20 Suppl 3, page: S4, stat: Journal Article,

The lysosomal cysteine protease, cathepsin S, is increased in Alzheimer's disease and Down syndrome brain. An immunocytochemical study
Lemere CA; Munger JS; Shi GP; Natkin L; Haass C; Chapman HA; Selkoe DJ
1995 Apr;146(4):848-860, American journal of pathology
— id: 35179, year: 1995, vol: 146, page: 848, stat: Journal Article,

Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S
Munger JS; Haass C; Lemere CA; Shi GP; Wong WS; Teplow DB; Selkoe DJ; Chapman HA
1995 Oct 1;311 ( Pt 1)(3):299-305, Biochemical journal
— id: 35178, year: 1995, vol: 311 ( Pt 1), page: 299, stat: Journal Article,

The role of thiol proteases in tissue injury and remodeling
Chapman HA Jr; Munger JS; Shi GP
1994 Dec;150(6 Pt 2):S155-S159, American journal of respiratory & critical care medicine
— id: 35180, year: 1994, vol: 150, page: S155, stat: Journal Article,

Human cathepsin S: chromosomal localization, gene structure, and tissue distribution
Sh