DNA Damage Response Pathways

ownload B4 is unusual among receptor tyrosine kinases because some isoforms can be efficiently cleaved at the a membrane to release a soluble intracellular domain. The cleavage product has high kinase activity mes to the nucleus. A screen for proteins that associate with the ErbB4 intracellular domain identified ate interactors including ITCH, WWP2, Nucleolin, and Krab-associated protein 1 (Kap1). Kap1 binds ltiple isoforms of ErbB4 but does not require ErbB4 kinase activity for binding, nor is it an ErbB4 ate. Kap1 reduces ERBB4 transcription and either directly or indirectly modulates the expression of genes e themselves regulated by ErbB4. Upregulation of ErbB4 and suppression of MDM2 jointly enhance and ate the accumulation of p21 in response to DNA damage. Overall, these findings further substantiate acceler the role of ErbB4 in conjoint regulation of growth factor signaling and DNA damage responses. Mol Cancer Res; 8(10); 1388–98. ©2010 AACR.