STAT‐mediated EGFR signaling in cancer

Abstract

The epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription (STATs) are commonly expressed and activated in many malignancies. EGFR is an upstream activator of several pathways involved in tumor progression, and STATs activate selected genes involved in oncogenesis. There are several different mechanisms by which STAT proteins can mediate intracellular EGFR signaling, including direct activation of STATs by EGFR binding and indirect activation of STATs through Src-mediated EGFR signaling. EGFR likely activates STAT in a manner distinctive from other mechanisms of STAT activation; STAT5 can be phosphorylated in an EGF-dependent manner at unique sites, conferring novel functions. Cumulative evidence suggests that targeting EGFR signaling pathways at several levels may demonstrate synergistic therapeutic effects compared with targeting the upstream receptor alone. Thus, methods to inhibit EGFR in conjunction with oncogenic STATs may represent a novel therapeutic strategy for cancers characterized by upregulation of EGFR signaling.

The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review

“…The assessment of the PI3K/AKT/mTOR pathway and its aberrant activation have been described in several human cancers, such as breast cancer, colorectal cancer, squamous cell carcinomas, angiosarcomas and soft tissue tumors (Castaneda et al 2010, Quesnelle et al 2007, Clark et al 2010, Lahat et al 2010, Dobashi et al 2009. After p53, the PI3K/AKT/mTOR is the most frequently activated pathway in neoplastic processes (Agarwal et al 2010).…”

Growth hormone (GH) modulation of Epidermal growth factor (EGF) signalling in human mammary epithelial cells

“…In humans, seven functionally and structurally related STAT proteins have been found . They all contain an oligomerization domain, a DNA binding domain and a Src homology 2 domain (SH2) (Quesnelle et al, 2007). In the mammary gland STAT-5a and STAT-5b are mostly expressed (Liu X et al, 1995;Kiu and Nicholson, 2012).…”

“…EGFR can activate STATs by direct binding through the SH2 domain or by EGFR-mediated activation of the protein tyrosine kinase Src (Src) (Fig.7). In case of direct STAT binding to EGFR, JAK is not necessary for activation (Quesnelle et al, 2007). (Rawlings et al, 2004).…”

Mutual Regulation of Receptor-Mediated Cell Signalling and Endocytosis: EGF Receptor System as an Example

“…Grb2 and SOCS can inhibit Statmediated EGFR signaling respectively, by either binding to the STAT activation site on EGFR or by binding to JAK to suppress Src activation of Stats. Once activated, Stats dimerize and translocate to the nucleus where they activate the transcription of genes involved in proliferation, differentiation, and survival [49]. Importantly, Src kinases, which have been reported to be activated in many cancers with high EGFR levels, have been shown to potentiate EGFR signaling [50][51][52].…”