Figure 7.

A. Biological model for role of Abi1-Iso2 in regulation of CrkY251 mediated Abl transactivation and cell invasion: Downstream of EGFR, which is amplified in classical GBM, CrkY251 becomes phosphorylated and drives Abl kinase transactivation that results in cell invasion. Loss of Abi1 and gain in Crk expression in GBM results in enhanced invasion via an amplified Crk-Abl transactivation pathway. B. Crk and Abi1 interact with Abl kinase with different itineraries: Proposed model by which Crk SH3N binds to the C-terminal PRD of Abl and leads to phospho Tyr 251 mediated Abl transactivation. In this partially open conformation model of Abl kinase, SH3 domain of Abi1-Iso2 competes with SH3N domain of Crk for binding to C-terminal proline-rich domain of Abl kinase. The Abi1-Abl kinase complex is further stabilized by interaction between N-terminal proline rich sequences of Abi1 and SH3 domain of Abl kinase and Abi1 pY213 and Abl SH2 domain. In homeostasis, relative stoichiometry of Crk-Abl kinase complexes and Abi1-Abl kinase complexes are regulated that creates a binary molecular switch mechanism, thus creating a fine-tuning system of Abl kinase activity.