The microenvironment in which cells reside in tissues, the extracellular matrix (ECM), is increasingly recognized as a major regulator of embryonic morphogenesis. We propose to use the Xenopus embryo as a model system to study a novel mechanism of regulation of ECM, the tyrosine phosphorylation of secreted proteins. In our preliminary experiments, we have identified a protein tyrosine kinase that, unlike any previously known tyrosine kinase, is synthesized directly into the secretory pathway, and which phosphorylates extracellular matrix proteins. Our preliminary data indicate that this novel kinase as a key role in early craniofacial patterning. The activity and location of this kinase provides the first explanation for a large body of published phosphoproteomic work reporting conserved tyrosine phosphorylations in ECM proteins secreted via the canonical signal peptide pathway. We plan to use frog embryos to study the function of this secreted tyrosine kinase in early craniofacial morphogenesis, and identify and characterize tyrosine phosphorylated substrates in an in vivo context. These studies will provide the basis for an entirely new area of study, the reversible regulation of secreted proteins by tyrosine phosphorylation during embryogenesis. Dynamic regulation and remodeling of ECM is also central to a wide range of disease pathologies (e.g. tumor metastasis, fibrosis, atherosclerosis), and therefore the regulation of ECM proteins by tyrosine phosphorylation is likely to also have important implications for the modulation of disease pathogenesis.

Public Health Relevance

We plan to study a newly identified mechanism of regulation of the extracellular environment during embryonic development. We are particularly interested in how this novel regulatory mechanism underlies the early establishment of craniofacial structure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE024312-01
Application #
8679884
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Scholnick, Steven
Project Start
2014-04-09
Project End
2016-03-31
Budget Start
2014-04-09
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$296,625
Indirect Cost
$121,625
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Bordoli, Mattia R; Yum, Jina; Breitkopf, Susanne B et al. (2014) A secreted tyrosine kinase acts in the extracellular environment. Cell 158:1033-44