Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops

Abstract

Grb2-associated binder 1 (GAB1) is a scaffold protein involved in numerous interactions that propagate signaling by growth factor and cytokine receptors. Here we explore in silico and validate in vivo the role of GAB1 in the control of mitogenic (Ras/MAPK) and survival (phosphatidylinositol 3-kinase (PI3K)/Akt) signaling stimulated by epidermal growth factor (EGF). We built a comprehensive mechanistic model that allows for reliable predictions of temporal patterns of cellular responses to EGF under diverse perturbations, including different EGF doses, GAB1 suppression, expression of mutant proteins, and pharmacological inhibitors. We show that the temporal dynamics of GAB1 tyrosine phosphorylation is significantly controlled by positive GAB1-PI3K feedback and negative MAPK-GAB1 feedback. Our experimental and computational results demonstrate that the essential function of GAB1 is to enhance PI3K/Akt activation and extend the duration of Ras/MAPK signaling. By amplifying positive interactions between survival and mitogenic pathways, GAB1 plays the critical role in cell proliferation and tumorigenesis.

Abnormal hematopoiesis in Gab2 mutant mice

“…37 Kiyatkin et al 37 used a computational model validated by in vivo experiments to demonstrate that Gab1 enhances the PI-3K signaling pathway. They explain this enhancement by the Grb2-mediated membrane recruitment of Gab1, which in turn binds PI-3K, allowing its activation.…”

Complexity of Receptor Tyrosine Kinase Signal Processing

“…RTK network topologies involve comprehensive and intricate regulatory structures of immediate and delayed feedback loops (Fig. 3) (Kiyatkin et al 2006;Amit et al 2007;Gotoh 2009;Lemmon and Schlessinger 2010;Sturm et al 2010;Avraham and Yarden 2011;Segatto et al 2011). …”

Theoretical Analysis of the Epidermal Growth Factor Receptor Signaling Network under the Control Condition and After Chronic Ethanol Treatment

“…Мы предварительно разработали и проанализировали кинетические модели различных ветвей EGFR сигнального пути при различных физиологических условиях [10,[12][13][14][15]. Они включают начальную часть EGFR пути [10,12], Ras активацию [13], цикл фосфорилирования-дефосфорилирования MAPK [14] и глубокую положительную обратную связь в PI3K-Gab1 сигнальном пути [15].…”

“…Эти исследования обеспечивают базу для интенсивного количественного анализа молекулярных механизмов, лежащих в основе чувствительности EGFR сигнальной машины к хроническому употреблению алкоголя. В данной работе мы, основываясь на наших предыдущих компьютерных исследованиях EGF-индуцируемых сигнальных ответов в гепатоцитах крыс [10,[12][13][14][15], используем комбинационное экспериментальное и теоретическое исследование, чтобы охарактеризовать изменения в EGFR-активируемой сигнализации крыс после долгого нахождения на алкогольной диете.…”