Type I transglutaminase is the enzyme that catalyzes formation of the crosslinked structure of the cornified envelope. Appropriate timing of onset and level of transglutaminase activity is absolutely required to achieve normal terminal differentiation. Abnormal activity of this enzyme leads to debilitating disease. For example, reduction in type I transglutaminase activity is the underlying defect in the disfiguring disease, lamellar ichthyosis. Previously, activity of this enzyme was believed to be solely controlled by the level of calcium in the extracellular environment. However, we recently identified a novel protein that is selectively expressed in the differentiated epidermal layers. Our preliminary studies suggest that this protein, TIG3, may control the timing and extent of activation of type I transglutaminase. We show that vector-mediated overexpression of TIG3 in keratinocytes enhances envelope formation. Our preliminary results indicate the remarkable finding that TIG3 preferentially activates type I transglutaminase activity by a direct interaction with the enzyme. A central goal of this proposal is to assess how this is achieved at a molecular level. Our workinq model is that TIG3 levels increase during keratinocyte differentiation, and that TIG3 then modulates transglutaminase activity to catalyze comeocyte formation and complete terminal differentiation. As TIG3 represents a new keratinocyte functional family, there is a great deal we do not understand about its function. The studies described in this proposal are designed to gain insights into its mechanism of action. An innovative aspect of this work is the characterization, using state of the art methods, of a new, completely novel, potentially important effector of keratinocyte terminal differentiation. We propose four aims designed to obtain fundamental information regarding TIG3 function.
Specific Aims 1 and 2 are designed to investigate the TIG3 mechanism of action and to identify important functional domains within the TIG3 protein.
Specific Aim 3 is designed to assess the importance of TIG3 subcellular distribution for function, and Specific Aim 4 is designed to investigate the TIG3 role in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049713-06
Application #
7414712
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Baker, Carl
Project Start
2004-08-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$183,986
Indirect Cost
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Scharadin, Tiffany M; Adhikary, Gautam; Shaw, Kristin et al. (2014) Pericentrosomal localization of the TIG3 tumor suppressor requires an N-terminal hydrophilic region motif. J Invest Dermatol 134:1220-1229
Scharadin, Tiffany M; Eckert, Richard L (2014) TIG3: an important regulator of keratinocyte proliferation and survival. J Invest Dermatol 134:1811-1816
Scharadin, Tiffany M; Jiang, Haibing; Martin, Stuart et al. (2012) TIG3 interaction at the centrosome alters microtubule distribution and centrosome function. J Cell Sci 125:2604-14
Jiang, Haibing; Jans, Ralph; Xu, Wen et al. (2010) Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis. J Biol Chem 285:31634-46
Rorke, E A; Adhikary, G; Jans, R et al. (2010) AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation. Oncogene 29:5873-82
Eckert, Richard L; Sturniolo, Michael T; Jans, Ralph et al. (2009) TIG3: a regulator of type I transglutaminase activity in epidermis. Amino Acids 36:739-46
Seo, Su-jean; Fields, Michele L; Buckler, Jodi L et al. (2002) The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells. Immunity 16:535-46