Intracellular signaling cascades activated by growth factors and integrins are known to drive development and differentiation in several tissues. Nevertheless, no information is available about such mechanisms in developing salivary glands. The earlier published and preliminary data show that engagement of both the epidermal growth factor receptor (EGFR) and integrins containing the alpha6-subunit are needed for branching morphogenesis of the fetal mouse submandibular gland (SMG). Several intracellular pathways activated by EGFR and/or integrins have been defined. The best characterized pathways signal via the RAS/MEK/ERK cascade, or phospholipase Cgamma1 (PLCgamma1), or phosphoinositol-3-kinase (PI3K). The latter two enzymes activate protein kinase C (PKC). The preliminary studies have already shown that the RAS/MEK/ERK pathway is necessary for branching morphogenesis of the SMG, and that its activity varies with fetal age. A system for analysis of branching morphogenesis of isolated fetal SMG epithelium cultured under fully defined conditions with Matrigel and know amounts of EGF has recently become available. The Major Hypothesis is that age-dependent variations in the activity of the three major signaling pathways triggered by EGFR and by integrins affect the course of development of the SMG by a dynamic regulatory circuit of positive signaling by ERK and PKB, balanced by negative signaling by PKC. There are plans to test this hypothesis by:
Specific Aim 1 : To establish that various PKC negatively regulate the EGFR in the fetal SMG.
Specific Aim 2 : To demonstrate that signaling via PLCgamma1 and PI3K have essential roles in branching morphogenesis.
Specific Aim 3 : To identify the PKC isozymes that regulates branching morphogenesis.
Specific Aim 4 : To define the regulatory roles of the EGFR and of the alpha6-containing integrins on specific signaling components controlling branching morphogenesis of the SMG. The proposed studies will have significance for understanding normal developmental mechanisms, for defining dysfunction leading to congenital malformations or to transformations resulting in carcinomas, and for advancing efforts on regeneration and tissue engineering of salivary glands.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010858-07
Application #
6516463
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Kousvelari, Eleni
Project Start
1995-04-01
Project End
2005-12-31
Budget Start
2002-04-01
Budget End
2002-12-31
Support Year
7
Fiscal Year
2002
Total Cost
$239,625
Indirect Cost
Name
City College of New York
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
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Barka, Tibor; Gresik, Edward S; Miyazaki, Yuji (2005) Differentiation of a mouse submandibular gland-derived cell line (SCA) grown on matrigel. Exp Cell Res 308:394-406
Barka, Tibor; Gresik, Edward S; Henderson, Scott C (2004) Production of cell lines secreting TAT fusion proteins. J Histochem Cytochem 52:469-77
Kurabuchi, Shingo; Gresik, Edward W; Hosoi, Kazuo (2004) Additive and/or synergistic action (downregulation) of androgens and thyroid hormones on the cellular distribution and localization of a true tissue kallikrein, mK1, in the mouse submandibular gland. J Histochem Cytochem 52:1437-46
Koyama, Noriko; Kashimata, Masanori; Sakashita, Hideaki et al. (2003) EGF-stimulated signaling by means of PI3K, PLCgamma1, and PKC isozymes regulates branching morphogenesis of the fetal mouse submandibular gland. Dev Dyn 227:216-26
Kurabuchi, Shingo; Hosoi, Kazuo; Gresik, Edward W (2002) Developmental and androgenic regulation of the immunocytochemical distribution of mK1, a true tissue kallikrein, in the granular convoluted tubule of the mouse submandibular gland. J Histochem Cytochem 50:135-45
Kashimata, M W; Sakagami, H W; Gresik, E W (2000) Intracellular signalling cascades activated by the EGF receptor and/or by integrins, with potential relevance for branching morphogenesis of the fetal mouse submandibular gland. Eur J Morphol 38:269-75
Barka, T; Gresik, E W; van Der Noen, H (2000) Transduction of TAT-HA-beta-galactosidase fusion protein into salivary gland-derived cells and organ cultures of the developing gland, and into rat submandibular gland in vivo. J Histochem Cytochem 48:1453-60
Kashimata, M; Sayeed, S; Ka, A et al. (2000) The ERK-1/2 signaling pathway is involved in the stimulation of branching morphogenesis of fetal mouse submandibular glands by EGF. Dev Biol 220:183-96
Kurabuchi, S; Da, J T; Gresik, E W et al. (1999) An unusual sexually dimorphic mosaic distribution of a subset of kallikreins in the granular convoluted tubule of the mouse submandibular gland detected by an antibody with restricted immunoreactivity. Histochem J 31:19-28

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