Shc‐dependent pathway is redundant but dominant in MAPK cascade activation by EGF receptors: a modeling inference

Abstract

In cell signaling cascades, one stimulus often leads to various physiological functions by multiple pathways. Perturbation of one pathway by blocking or overexpressing one of its components will result in changes in multiple pathways and multiple cell functions. Thus, it is important to reveal the relative contribution of each pathway to each function in order to assess the consequence of perturbations (e.g. drug delivery). By exploring an established mathematical model, the Shc-dependent pathway is found to be both redundant and dominant during activation of the mitogen-activated protein kinase cascade by epidermal growth factor receptor (EGFR). Its dominance results from the majority consumption of the common precursor ((EGF-EGFR*)2-GAP) by this pathway. The key steps for the dominance are the binding and phosphorylation of Shc. In conclusion, cells may prefer the long Shc-dependent pathway to the short Shc-independent pathway. ß

The role of EGFR and ErbB family related proteins in the oligodendrocyte specification in germinal niches of the adult mammalian brain

“…Following activation of EGFR, the SH2 domain of Grb2 can bind to the EGFR either directly (via Y1068 and Y1086) or indirectly via tyrosine phosphorylated Shc (Sasaoka et al, 1994). The association of Shc to EGFR through its PTB domain recruits Grb2 and constitutes one of the main steps in EGF-dependent induction of the Ras/MAPK pathway (Gong and Zhao, 2003). Heterodimerization between different ErbB family members generates a number of cellular effects (Figure 5).…”

Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway

“…For example, the Kholodenko et al [60] model has been used as a basis for many other models of the EGFR system [41,46,48,51]. The Schoeberl et al [42] model has since been analysed further in a number of studies [66][67][68][69]; for example, Gong and Zhao [66] investigated the relevance of the Shc-dependent and Shc-independent pathways; it has also been combined with data on metalloprotease activation to build a model of autocrine signal transduction by cancer cells exposed to ionizing radiation [70]. The Schoeberl et al [42] model has since been analysed further in a number of studies [66][67][68][69]; for example, Gong and Zhao [66] investigated the relevance of the Shc-dependent and Shc-independent pathways; it has also been combined with data on metalloprotease activation to build a model of autocrine signal transduction by cancer cells exposed to ionizing radiation [70].…”

Phosphorylation of the epidermal growth factor receptor (EGFR) is essential for interleukin-8 release from intestinal epithelial cells in response to challenge with Escherichia coli O157 : H7 flagellin

“…to be dominant but not essential for activation of the MAPKs ERK1/2 and p38 (Gong & Zhao, 2003). The kinetics of EGFR phosphorylation events have been examined in Caco-2 cells in response to other nonmicrobial stimuli, such as bile acids (Raimondi et al, 2008), and the early spike in EGFR tyrosine phosphorylation in response to EGF has been described elsewhere (Zhang et al, 2005).…”