Jonathan A. Cooper

Appointments and Affiliations

 
 
Fred Hutchinson Cancer Research Center
Senior Vice President and Director
Basic Sciences Division
 
Fred Hutchinson Cancer Research Center
Basic Sciences Division
Member
 
University of Washington
School of Medicine
Biochemistry
Affiliate Professor
Professional Headshot of Jonathan A. Cooper

Mailing Address

Fred Hutchinson Cancer Research Center
1100 Fairview Avenue N.
A2-025
Seattle, Washington 98109
United States

Contact

Phone: (206) 667-4454
Fax: (206) 667-6522
jcooper@fhcrc.org
http://labs.fhcrc.org/cooper/index.html
 

Degrees

Ph.D., University of Warwick, 1976.
B.A., University of Cambridge, 1973.

Research Interests

Signaling Pathways in Development and Cancer

We are interested in the signaling pathways that regulate cell migrations and malignant transformation. We study these functions in cultured vertebrate cells and in genetically-engineered mice.

1. Dab1, Src family kinases and neuron migrations

We have found that a Src-substrate, Dab1, regulates neuron migrations during mammalian brain development. Two lipoprotein receptors expressed on CNS neurons have partially redundant roles in binding a signaling molecule called Reelin. Clustering of these receptors by Reelin induces the tyrosine phosphorylation of Dab1 by Src and its close relative Fyn. This phosphorylation is essential for proper migration of post-mitotic neurons before they undergo terminal differentiation. In mice that are mutant for Dab1, or for both Src and Fyn, the neurons differentiate in incorrect locations within the developing brain. We are characterizing the pathways that link Dab1, Src and Fyn to the migration machinery. One pathway involves PI3 kinase and Akt. Another involves the Crk and CrkL adaptor proteins and tyrosine phosphorylation of the C3G Rap1 guanine nucleotide exchange factor. We have evidence that Dab1 has two important functions: one is to activate Src and Fyn and the other is to act as a scaffold to assemble signaling complexes. Both functions are needed for normal development. We have also discovered a mechanism that turns off signaling by phosphotyrosine-dependent polyubiquitination and degradation of Dab1. Neuron migrations are uniquely affected when pathway inactivation is prevented in vivo. We are using neuron cultures, in utero electroporation of DNA into developing fetal brain, and genetically-engineered mice to dissect the signaling mechanism and underlying cell biology.

2. Dab2 and cellular transport

Dab2 is a clathrin-associated sorting protein (CLASP) that is related to Dab1. Dab2 plays an important role in endocytosis of specific cell surface receptors, including beta integrins, which mediate cell-matrix interactions, and lipoprotein receptors, which frequently act as co-receptors or endocytic receptors for signaling molecules. Dab2 binds to cell membranes, receptors, clathrin and accessory proteins and brings these proteins together to form a clathrin-coated pit. Dab2 expression is commonly down-regulated in cancer cells, possibly due to selection for altered traffic of cell surface receptors.

3. Src family kinases

Many human tumors have increased Src kinase activity. However, activating mutations in the Src gene are exceedingly rare, suggesting that Src kinase activity is up-regulated due to changes in other genes. We have found that Src is activated, and cells become transformed, when a phosphotyrosine-dependent ubiquitin ligase complex, the Cul5-CRL, is down-regulated. Cul5 accelerates the degradation of active Src and some of its tyrosine-phosphorylated targets, thus decreasing the strength and shortening the duration of Src signals. Experiments are underway to identify key Cul5 targets that promote Src-dependent transformation when Cul5 is absent.

Previous Positions

1995-2000, Co-Director, University of Washington, Graduate Program in Molecular and Cellular Biology
1995-2000, Co-Director, Fred Hutchinson Cancer Research Center, Graduate Program in Molecular and Cellular Biology

 

Recent Publications

2017
2016
2015
2014
2013
2012
2011
2010
2009

Coming Soon: New Profiles System!

In preparation for the launch of our new profiles system, we are freezing updates to these profiles. If you have any questions, please email library@fredhutch.org.

Researcher Profiles

 

Related Websites

 

Scientific Divisions