Biography
Research Interests:
Functions and regulation of Eph receptor tyrosine kinases
Although there is only a single Eph receptor tyrosine kinase (VAB-1) encoded by the C. elegans genome, this family of receptors has undergone a remarkable expansion during the course of metazoan evolution to include at least 14 vertebrate members. Eph receptors regulate a variety of complex cellular interactions; they are involved in processes such as morphogenetic movements, axon guidance, topographic mapping, synaptic plasticity, boundary formation, and angiogenesis. Mammalian Eph receptors are divided into two groups-A and B-based on their abilities to interact with their ligands (termed ephrins). A-type ephrins are themselves associated with the cell surface through a GPI anchor. B-type ephrins have a transmembrane region and a highly conserved cytoplasmic sequence that, upon ephrin binding to an Eph receptor, becomes phosphorylated on tyrosine. A combination of genetic and biochemical analyses indicate that Eph receptors have both kinase-dependent and kinase-independent functions. The kinase-independent activities of Eph receptors require their association with ephrins and may be mediated either through cell adhesion or by signaling from the ephrin itself. The kinase-dependent signaling pathways activated by Eph receptors are in part targeted to the cytoskeleton, and regulate events such as growth-cone retraction. A structure-function analysis of the EphB2 receptor has identified sequences in the receptor's cytoplasmic region that are required for kinase activation and association with downstream targets. Surprisingly, autophosphorylation within the non-catalytic juxtamembrane region of the receptor is involved not only in binding to SH2 domain signaling proteins, but also in control of kinase activation. The x-ray crystal structure of the kinase and juxtamembrane regions of EphB2 has revealed an entirely novel mechanism through which Eph receptor tyrosine kinases are regulated by the unphosphorylated juxtamembrane region, and the means by which tyrosine phosphorylation relieves this autoinhibition. This regulatory mechanism may have general relevance for growth factor receptors.
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