Abstract

FGF signaling is essential for lung morphogenesis. During years 06-10 of this grant, we have shown that the murine and indeed the human sprouty gene family function as important, highly conserved, inducible negative modulators of FGF signaling in respiratory branching morphogenesis. Recently, we and others have further discovered that tyrosine phosphorylation is critical for Sprouty function. Now our new preliminary data show that the tyrosine phosphatase Shp2, as well as FRS2, which are both required for FGF signaling, reversibly bind mSpry2. Hypothesis: Shp2 protein tyrosine phosphatase plays a critical role in finely modulating mSpry2 function, in a supra-molecular assembly with FRS2, within the FGF signaling complex, which is essential for lung morphogenesis.
Aim 1 : To determine and compare the spatial and sub-cellular co-distribution of mSpry2 with Shp2, FRS2 and other key FGF signaling elements during lung morphogenesis.
Aim 2 : To determine the functional role of Shp2 and FRS2 in lung morphogenesis in culture.
Aim 3 : To determine the relative functional contribution of mSpry2, Shp2 and FRS2 in lung morphogenesis by complementation of FGF10 hypomorphism.
Aim 4 : To determine the role of tyrosine phosphorylation in protein-protein interaction and supra-molecular assembly of mSPRY2 with SHP2 and FRS2.
Aim 5 : To determine the functional importance of Shp2 in lung morphogenesis in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044977-15
Application #
7174282
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
1991-08-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
15
Fiscal Year
2007
Total Cost
$361,020
Indirect Cost

  Institution

Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027

  Publications

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
Turcatel, Gianluca; Rubin, Nicole; El-Hashash, Ahmed et al. (2012) MIR-99a and MIR-99b modulate TGF-* induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One 7:e31032
El-Hashash, Ahmed H K; Warburton, David (2012) Numb expression and asymmetric versus symmetric cell division in distal embryonic lung epithelium. J Histochem Cytochem 60:675-82
Sala, Frederic G; Del Moral, Pierre-Marie; Tiozzo, Caterina et al. (2011) FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138:273-82
Jackson, Sha-Ron; Lee, Jooeun; Reddy, Raghava et al. (2011) Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol 300:L898-909
El-Hashash, Ahmed H K; Al Alam, Denise; Turcatel, Gianluca et al. (2011) Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 353:242-58
El-Hashash, Ahmed H K; Al Alam, Denise; Turcatel, Gianluca et al. (2011) Eyes absent 1 (Eya1) is a critical coordinator of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 350:112-26
El-Hashash, Ahmed H; Warburton, David (2011) Cell polarity and spindle orientation in the distal epithelium of embryonic lung. Dev Dyn 240:441-5
El-Hashash, Ahmed H K; Turcatel, Gianluca; Al Alam, Denise et al. (2011) Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development 138:1395-407
Tarantal, A F; Chen, H; Shi, T T et al. (2010) Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis. Eur Respir J 36:907-14

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