Mechanisms of Receptor Tyrosine Kinase Inhibition

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DESCRIPTION (provided by applicant): Growth factor receptor tyrosine kinases (RTKs) play central roles in the development and maintenance of tissues, and their aberrant activation contributes to the growth and progression of a variety of tumor types. The long-term goal of the proposed project is to identify and characterize novel RTK negative regulatory pathways in an effort to better understand the mechanisms by which RTKs contribute to tumor progression. Efforts for the current funding period will focus on a novel human transmembrane leucine-rich repeat protein called LRIG1. LRIG1 physically interacts with each of the four members of the mammalian ErbB family of RTKs, enhances their ubiquitination and degradation, and suppresses ErbB-mediated proliferation and transformation of cultured cells. Our two overarching questions concern the biochemical mechanisms underlying ErbB negative regulation by LRIG1, and the participation of LRIG1 in ErbB signaling in vivo. These questions will be addressed with four specific aims. 1) The mechanisms underlying LRIG1-mediated receptor ubiquitination and degradation will be assessed by identifying the responsible E3 ubiquitin ligase(s). 2) Mutagenesis approaches will be employed to functionally dissect the LRIG1 molecule to identify regions responsible for interacting with ErbB receptors, and regions responsible for coupling receptors to the protein degradation machinery. Receptor structural elements responsible for LRIG1 interaction will also be identified. 3) The ability of LRIG1 to influence ErbB-mediated mammary tumor progression in a transgenic mouse model will be examined. These studies will involve crossing LRIG1-/- mice or mice inducibly overexpressing LRIG1 into an MMTV-ErbB2 line, and assessing tumor latency, growth rate and metastasis frequency. 4) The expression of LRIG1 in human breast tumors will be examined and correlated with ErbB receptor protein overexpression. The proposed project will lay the biochemical foundation for LRIG1 as a negative regulator of ErbB receptor function.