Nuclear functions of receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are well-known cell surface receptors that play important roles in normal cellular processes by binding to many growth factors and cytokines. Abnormal expression and mutations of these RTKs have been implicated in the development of many diseases including cancers. More recently, accumulated studies have shown that 11 of total 20 RTK subfamilies are detected in the nucleus, including the EGFR family, VEGFR family, FGFR family, insulin receptor family, Eph family, HGF receptor family, and ROR family as well as Trk, Ryk, and Mer receptor tyrosine kinases. These observations of nuclear-localized RTKs and functional studies demonstrate that RTKs function not only on the cell surface but also in the nucleus. Thus, it has become increasingly important to understand how the cell surface receptors are trafficked to the nucleus and how these receptors function in the nucleus. Several studies have shown that nuclear RTKs are involved in transcriptional regulation, DNA damage response, DNA replication, and drug resistance. In addition, a membrane-associated trafficking mechanism has been reported, which provides a comprehensive pathway for nuclear translocation of EGFR. This trafficking route may serve as a general mechanism for other cell surface receptors for the nuclear transport. In this chapter, we will focus the functional study of nuclear RTKs and summarize the physiological and pathological functions of RTKs in the nucleus.