Receptor Tyrosine Kinases in the Nucleus

Abstract

To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

An Overdose of the Arabidopsis Coreceptor BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE1 or Its Ectodomain Causes Autoimmunity in a SUPPRESSOR OF BIR1-1-Dependent Manner

“…For example, cleavage of the TOLL-LIKE RECEPTOR9 ectodomain allows a key conformational change required for activation . The epidermal growth factor receptor is modified at the transmembrane domain to release an active intracellular domain: the latter is translocated to the nucleus, where it may regulate gene expression (Carpenter and Liao, 2013). In plants, cleavage at the ectodomain has been proposed for several RLKs, like the rice PRR Xa21, the Arabidopsis regulator CHITIN ELICITOR RECEPTOR KINASE1, and the symbiotic receptor kinase from Lotus japonicus (Park and Ronald, 2012;Antolín-Llovera et al, 2014;Petutschnig et al, 2014).…”

“…by proteolytic cleavage) is sometimes necessary for full receptor activation (Bauer, 2013;Carpenter and Liao, 2013). For example, cleavage of the TOLL-LIKE RECEPTOR9 ectodomain allows a key conformational change required for activation .…”

Effective implementation of novel MET pharmacodynamic assays in translational studies

“…Many receptor tyrosine kinases (RTKs) (e.g., EGFR, FGFR, VEGFR, ERRB2, and IGF1R) are known to translocate to the nucleus in response to ligand stimulation or oxidative stress to regulate transcription of genes (27,28), and similarly the role of MET in the nucleus is beginning to be elucidated.…”

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

“…Figure 2 illustrates the proposed trafficking pathway of full-length ErbB-2 to the nucleus, induced by either HRG binding to ErbB-3, which leads to the formation of ErbB-2/ErbB-3 dimers and ErbB-2 activation or by constitutive ErbB-2 activation induced by the formation of ErbB-2 homodimers. The mechanisms of ErbB-2 nuclear translocation has been extensively reviewed elsewhere (Giri et al 2005, Wang et al 2010b, Carpenter & Liao 2013, Bertelsen & Stang 2014, Chen & Hung 2015. In spite of all these findings highlighting nuclear ErbB-2's key role in BC and providing a mechanistic explanation for its nuclear trafficking, the clinical significance of nuclear ErbB-2 remains almost unexplored.…”

“…Remarkably intriguing were also their findings revealing that the carboxyl terminus of p185 neu displays transactivation activity when tested in a GAL4-reporter assay. More than twenty years have gone by since this initial discovery, which was followed by numerous other findings identifying nuclear presence of as many as 18 distinct RTKs so far (reviewed in Carpenter & Liao 2013). We have come a long way since the days when the notion of ErbBs in the nucleus was so utterly challenging that it was regarded as either 'ridiculous or sublime' (Waugh & Hsuan 2001).…”