Development and tissue differentiation isdictated by secreted growth and differentiation factors. Among these, members of the TGF-beta superfamily are well known to play key roles. TGF-beta and related proteins also play key roles in normal lung development, while TGF-beta itself plays an important role in the response to injury. TGF-beta expression and signaling also contributes to pathobiology of some lung diseases and to carcinoma development and progression. Consequently the mechanisms of TGF-beta signaling have been of great interest in both normal development and in pathology. TGF-beta and related proteins signal through heteromeric, cell surface complexes of two types of transmembrane serine-threonine kinase receptors, which in turn activate, through phosphorylation, the Smads. Smad proteins act as intracellular effectors of TGF-beta signals that, following activation and heteromerization, translocate into the nucleus where they elaborate the ligand-induced transcription responses of many genes. The TGF-beta-induced Smad signaling pathway is now well accepted and its model of activation and mechanism of action are well developed. Increasing evidence, however, points out that the TGF-beta activation of the receptor complex also initiates other, non-Smad signaling pathways. Some of these observations are now being recognize, but very little is known about these non-Smad signaling mechanisms, how they link to receptors and what role they play inthe TGF-beta induced cellular response. Some of these parallel pathways may directlyregulate Smad signaling,while others may effect unrelated responses. This research proposal works from the hypothesis that these TGF-beta-induced non-Smad signaling pathways greatly contributeto the cellular response to TGF-beta and related factors. We propose to initiatea research program aimed at defining several TGF-beta-induced non-Smad signaling pathways, thereby specifically focusing on the activation of Erk MAP kinase, p38 MAP kinase, JNK and RhoA signaling in response to TGF-beta. The four Aims of this proposal will study how the activtion of these pathways is biochemically and mechanistically linked to the activation of the TGF-beta receptors and how they affect the cellular response to TGF-beta at the level of Smad activation and gene expression. Together, these studies should provide insight into the mechanisms of action of TGF-beta and related factors in normal development and inpathobiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060231-09
Application #
7615587
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$398,035
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Li, Changgong; Li, Aimin; Xing, Yiming et al. (2013) Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signaling. Dev Biol 378:13-24
Gong, Dapeng; Fei, Fei; Lim, Min et al. (2013) Abr, a negative regulator of Rac, attenuates cockroach allergen-induced asthma in a mouse model. J Immunol 191:4514-20
Gong, Dapeng; Shi, Wei; Yi, Sun-ju et al. (2012) TGF? signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol 13:31
El-Hashash, Ahmed H K; Turcatel, Gianluca; Varma, Saaket et al. (2012) Eya1 protein phosphatase regulates tight junction formation in lung distal epithelium. J Cell Sci 125:4036-48
Xu, Pinglong; Liu, Jianming; Derynck, Rik (2012) Post-translational regulation of TGF-* receptor and Smad signaling. FEBS Lett 586:1871-84
Tiozzo, Caterina; Danopoulos, Soula; Lavarreda-Pearce, Maria et al. (2012) Embryonic epithelial Pten deletion through Nkx2.1-cre leads to thyroid tumorigenesis in a strain-dependent manner. Endocr Relat Cancer 19:111-122
Lamouille, Samy; Connolly, Erin; Smyth, James W et al. (2012) TGF-?-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259-73
Xu, Pinglong; Liu, Jianming; Sakaki-Yumoto, Masayo et al. (2012) TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34

Showing the most recent 10 out of 126 publications