Tony Hunter
e-mail: hunter@salk.edu |
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Our goal is to understand the molecular basis of cell growth control and cell cycle regulation. Many growth factor receptors are protein-tyrosine kinases (PTK), which are activated by ligand-induced dimerization. Mitogenic signalling by PTKs involves tyrosine phosphorylation of critical target proteins. We have identified phospholipase Cg and the SH2/SH3 adaptor protein, Nck, as PTK targets, and shown that the c-Src nonreceptor PTK is essential for mitogenic signalling by the PDGF receptor PTK. We are currently investigating what signals lie downstream of Nck and c-Src. We are also studying what signalling pathways are activated when integrin receptors bind to extracellular matrix proteins, such as fibronectin, in mammalian cells. We are focusing on the roles of the focal adhesion kinase (FAK) PTK and its relative Pyk2, which are activated upon adhesion. We have also identified a Drosophila FAK/Pyk2 homologue, DmFAK, and we are carrying out a genetic analysis of its function.
To complement our work on PTKs, we are
investigating the functions of protein-tyrosine phosphatases (PTPs)
in cell signalling. We are studying the receptor-like PTP, RPTPa, which
like most RPTPs has a twin catalytic domain structure. The crystal structure
of the membrane proximal catalytic domain of RPTPa shows that it exists
as an inactive dimer, suggesting that dimerization of RPTPa, and other
RPTPs, may negatively regulate their activity. We are have shown that
this is true for the CD45 RPTP, and have evidence that RPTPa activity
is also inhibited by dimerization. This principle of regulation would
be the exact opposite of that observed for receptor PTKs. Our studies
on the role of phosphorylation in mammalian cell cycle regulation are
focused on the cyclin-dependent kinases (Cdk), and their substrates
and inhibitors, and on the Cdc7/Dbf4 kinase. Using a new protein kinase
substrate screen, we have identified Prc1, a spindle-associated protein,
as a Cdk substrate, and we have also shown that Cdc6, an essential component
of the prereplication complex that is bound to chromosomal origins,
is phosphorylated by cyclin E/Cdk2 resulting in its export from the
nucleus, thus preventing rereplication. We have identified a novel peptidyl-prolyl
isomerase, Pin1, that contains a WW domain and a prolyl isomerase domain.
Pin1 is the functional homologue of yeast Ess1p, a protein essential
for progression through mitosis, and Pin1 is essential for G2/M progression
in cultured cells. We have solved the structure of Pin1, and shown that
it binds to phosphorylated Ser.Pro sequences, which are generated by
Cdk phosphorylation. We are studying the role of Pin1 in cell cycle
progression.
Schlaepfer, D. D., Jones, K. C. and Hunter, T. 1998. Multiple Grb2-mediated integrin-signaling pathways to ERK2 MAP kinase: summation of both c-Src and FAK-initiated tyrosine phosphorylation events. Mol. Cell. Biol. 18:2571-2585.
Blume-Jensen, P., Janknecht, R. and Hunter. T. 1998. The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr. Biol. 8:779-782.
Janknecht, R., Wells, N. J. and Hunter, T. 1998. TGF-b-stimulated cooperation of Smad proteins with the coactivators CBP/p300. Genes Dev. 12:2114-2119.
Fukunaga, R. and Hunter, T. 1997. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method to identify protein kinase substrates. EMBO J. 16:1921-1933.
Ranganathan, R., Lu, K. P., Hunter, T. and Noel, J. 1997. Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell 89:875-886.
Jiang, W. and Hunter, T. 1997.
Identification and characterization of a human protein kinase related
to budding yeast Cdc7p. Proc. Natl. Acad. Sci. USA 94:14320-14325.
Tony Hunter received his Ph.D. from the University of Cambridge and held a fellowship at Christ's College in Cambridge. Dr. Hunter serves on many journal editorial boards and scientific advisory committees. He was elected to the National Academy of Science in 1998.
