1. Receptor Tyrosine Kinase Signaling

A long-term interest in the laboratory is to elucidate how transcriptional circuitries operating downstream of conserved signaling pathways mediate context-specific developmental responses. One particular focus is the Receptor Tyrosine Kinase (RTK) signaling pathway and the ETS transcription factors that serve as downstream effectors. Reflecting their critical roles in regulating cell proliferation, differentiation, apoptosis, migration, and epithelial-mesenchymal interactions during normal development, misregulated ETS proteins contribute, via a variety of mechanisms, to both the initiation and progression of many human cancers.

Among the best characterized ETS family transcriptional regulators and RTK pathway effectors are the Drosophila proteins encoded by pointed and yan. Pointed functions as a transcriptional activator while yan encodes a repressor that competes with Pointed for access to the regulatory regions of target genes. In response to RTK activation, MAPK-mediated phosphorylation abrogates Yan repressor activity, allowing Pointed to turn on genes formerly repressed by Yan. Both Yan and Pointed are evolutionarily conserved, and their respective mammalian orthologs Tel1 and Ets1/Ets2 also serve as critical regulators of RTK signaling and have been characterized as oncoproteins.

In vitro experiments have shown that Yan and its human ortholog Tel1 can form long polymers via homotypic interactions mediated by their N-terminal SAM domains. This observation has led to the hypothesis that polymerization could facilitate transcriptional repression by promoting/stabilizing long-range association with DNA. However, whether polymerization actually occurs in vivo and what its physiological role is remain open questions. Toward this goal, current studies in the laboratory seek to:

1. Identify direct transcriptional targets repressed by Yan and activated by Pointed and to determine the requirement for Yan self-association in regulating these genes during embryonic and retinal development.
2. Elucidate the mechanism of Yan-mediated repression by purifying and characterizing protein complexes under varying signaling conditions.
3. Investigate Yan polymerization in vivo using live imaging of fluorescently tagged proteins and reconstitute an in vitro system to investigate polymerization dynamics along DNA.

Related Publications

1.	Vivekanand P, Rebay I. Intersection of signal transduction pathways and development. Annu Rev Genet. 2006;40:139-57. Review.
2.	Vivekanand P, Tootle TL, Rebay I. MAE, a dual regulator of the EGFR signaling pathway, is a target of the Ets transcription factors PNT and YAN. Mech. Dev. 2004 Dec;121(12):1469-79.
3.	Qiao F, Song H, Kim CA, Sawaya MR, Hunter JB, Gingery M, Rebay I, Courey AJ, Bowie JU. Derepression by depolymerization; structural insights into the regulation of YAN by MAE. Cell. 2004 Jul 23;118(2):163-73.
4.	Tootle TL, Lee PS, Rebay I. CRM1-mediated nuclear export and regulated activity of the Receptor Tyrosine Kinase antagonist YAN require specific interactions with MAE. Development. 2003 Mar;130(5):845-57.