Tyrosine kinases control cell proliferation, differentiation, migration and survival, and are often deregulated in cancer. We are investigating Src proto-oncogene dependent cell migrations during mammalian development. Our past results showed that a Src-dependent signaling mechanism regulates the precise positioning and layering of cells in the developing mouse brain. Our more recent results provide evidence for a Src signaling event that increases membrane-localized N-cadherin on randomly-moving multipolar neurons in the neocortex. N-cadherin then enables directional cell migration. We also discovered the importance of tyrosine phosphorylation-dependent protein turnover in terminating neuron migrations in the cortex, and extended this finding to show that a similar process inhibits Src-dependent tumorigenesis. Therefore we propose to investigate three innovative hypotheses: (1) That a secreted signaling molecule, Reelin, increases surface N- cadherin levels by altering traffic (endo-/exocytosis) or inducing stabilization of surface N-cadherin. (2) That multipolar cells interpret direction signals from the environment through N-cadherin itself or through a cadherin- associated co-receptor. The direction signal may be conveyed by cell-cell contact or by a diffusible signal. (3) That the final positions of cortical neurons are determined by the timely cessation of Reelin-dependent terminal translocation, which stops when Cullin5-dependent mechanisms destroy the Src substrate, Dab1. Progress in these Aims will reveal molecular mechanisms underlying complex cell migrations in vivo.

Public Health Relevance

Src kinases are tightly regulated enzymes that normally control development of the embryo and homeostasis of the adult, yet Src de-regulation leads to cancer. This proposal will investigate a key developmental function of Src in controlling the movements of immature neurons in the brain during development. Past research led to the discovery of a pathway that inhibits Src during development and also in cancer. The future aims address other new aspects of cell biology discovered in the brain development system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
9R01NS080194-27
Application #
8244894
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Owens, David F
Project Start
1986-01-01
Project End
2017-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
27
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$166,250
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Teckchandani, Anjali; Laszlo, George S; Simo, Sergi et al. (2014) Cullin 5 destabilizes Cas to inhibit Src-dependent cell transformation. J Cell Sci 127:509-20
Cooper, Jonathan A (2014) Molecules and mechanisms that regulate multipolar migration in the intermediate zone. Front Cell Neurosci 8:386
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Simo, Sergi; Cooper, Jonathan A (2013) Rbx2 regulates neuronal migration through different cullin 5-RING ligase adaptors. Dev Cell 27:399-411