RESUMO
Cancer cells encounter stresses during tumor progression and metastatic spread, however, how they survive these challenges is not fully understood. We now identify a mechanism for cancer cell survival through the discovery of a multiprotein signaling complex that includes the GTPase Cdc42, the Cdc42 GEF/effector protein Dock7, AKT, mTOR and the mTORC1 regulatory partners TSC1, TSC2, and Rheb. This pro-survival signaling complex sustains the activated state of AKT by preventing its dephosphorylation at Ser473 during serum starvation, resulting in a low but critical activation of a Raptor-independent mTOR/S6K activity. We demonstrate that the Dock7 DHR1 domain, previously of unknown function, is responsible for preserving AKT phosphorylation through an interaction requiring its C2-like motif. Collectively, these findings help address long-standing questions of how Cdc42 signals mTOR activation by elucidating the unique functions of its signaling partner Dock7 as an AKT regulator necessary for resistance to anoikis and apoptosis in cancer cells.
RESUMO
The study of isolated airway myocytes has provided important information relative to specific processes that regulate contraction, proliferation, and synthetic properties of airway smooth muscle (ASM). To place this information in physiological context, however, improved methods to examine airway biology in vivo are needed. Advances in genetic, biochemical, and optical methods provide unprecedented opportunities to improve our understanding of in vivo physiology and pathophysiology. This article describes 4 important methodologic advances in the study of ASM: (1) the development of transgenic mice that could be used to investigate ASM proliferation and phenotype switching during the development of hypersensitivity, and to investigate excitation-contraction coupling; (2) the use of CD38-deficient mice to confirm the role of CD38-dependent, cyclic adenosine diphosphate-ribose-mediated calcium release in airway responsiveness; (3) investigation of the role of actin filament length and p38 mitogen-activated protein kinase activity in regulating the mechanical plasticity-elasticity balance in contracted ASM; and (d) the use of bronchial biopsies to study ASM structure and phenotype in respiratory science.
