Abstract SY23-02: RTK endocytosis and other feedback mechanisms in cancer

Abstract

Abstract The view of signal transduction pathways as a set of parallel pipelines connecting transmembrane receptor tyrosine kinases (RTKs) and the genome has given way, over the last decade, to the notion of layered networks, highly rich in internal connections. This paradigm is well exemplified by the RTK subfamily called ERBB, namely receptors for growth factors of the EGF (epidermal growth factor) and neuregulin groups: whereas ERBB-1 (also called EGFR) binds seven different growth factors and ERBB-4 binds several isoforms of neuregulins, ERBB-2/HER2 binds no known growth factor and the kinase activity of ErbB-3/HER3 is almost dead. Because both EGFR and HER2 frequently display aberrant expression and mutant forms in human tumors, their mode of action and regulation are of interest. Like other autonomous bi-stable systems, the ERBB network is regulated by feedback loops, both positive and negative. For example, one outcome of activation by growth factors is the transcriptional induction of EGF-like molecules (positive feedback). On the other hand, once activated the receptors are rapidly endocytosed and degraded in lysosomes (negative feedback). According to recent studies, negative feedback loops are often defective in tumors, whereas positive loops are frequently enhanced. In general, negative feedback regulation may be divided into two temporal phases: the immediate phase (approximately 20 minutes from stimulation) comprises posttranslational protein modifications, such as protein phosphorylation and ubiquitylation, as well as intracellular translocations of enzymes and adaptor proteins, including receptor endocytosis. The late phase of feedback regulation harnesses the transcriptional machinery, and it comprises newly synthesized proteins (e.g., phosphatases of the mitogen-activated protein kinases, MKPs), which restrain signaling. Interestingly, microRNAs complement the roles played by mRNA synthesis: multiple microRNAs undergo rapid turnover within minutes after growth factor stimulation, while another set is newly synthesized. In addition to the immediately down-regulated microRNAs (ID-miRs) and E3 ubiquitin ligases like CBL and Nedd4 family members, the first phase of negative RTK regulation entails tyrosine phosphatases like DEP-1, which dephosphorylates EGFR, and de-ubiquitinating enzymes (DUBs). E3 ligases, in concert with ubiquitin-binding proteins, which nucleate four different endosomal sorting complexes called ESCRTs, coordinate receptor sorting for either lysosomal degradation or recycling to the plasma membrane. In line with their negative regulatory functions, certain components of ESCRTs have been implicated in tumor suppression, and, on the other hand, inactive forms of the RTK-specific E3 ligase, namely CBL, are oncogenic. In analogy with regulators of the endocytic pathway, the group of immediate early genes (IEGs; e.g., FOS and JUN), which is induced by growth factors within the first 30 minutes, is endowed with an oncogenic potential. Likewise, tumors of epithelial and brain origins deviate from the physiological tight regulation of the IEGs: both ID-miRs and several RNA- and DNA-binding proteins, collectively termed delayed early genes (DEGs; e.g., the RNA-binding protein ZFP-36) shape the pulse like profile of IEG induction, but transformed cells escape this type of regulation. In summary, the emerging landscape of feedback regulation in malignant cells proposes multi-site manipulation of systems control: RTKs are often derailed to a recycling route by means of hyperactive RAB-coupling proteins (e.g., RAB11FIP1) and other aberrations, while both the ID-miRs and the DEGs are frequently down-regulated in tumors. Collectively, these aberrations enhance cytoplasmic signaling and augment expression of oncogenic transcription factors, which result in accelerated cell proliferation and higher invasiveness. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY23-02. doi:10.1158/1538-7445.AM2011-SY23-02