Signaling by ErbB Receptors in Breast Cancer: Regulation by Compartmentization of Heterodimeric Receptor Complexes

摘要

MEK kinase 1 (MEKKl) is a serine threonine kinase that induces apoptosis. Activation of specific apoptotic pathways leads to cleavage of MEKKl by caspase 3-like proteases into a 9lkDa fragment containing the kinase domain. Upon cleavage, MEKKl activates the caspase 3-like proteases in a feedback loop leading to apoptosis. MEKKl is also cleaved into the 9lkDa kinase domain in response to genotoxic agents such as etoposide or ultraviolet irradiation (Uv). Thus, overexpression of kinase inactive MEKKl inhibits both etoposide and UV- induced apoptosis. Akt is an anti-apoptotic serine threonine kinase that inhibits both etoposide and Uv- induced apoptosis. We show that Akt blocks MEKKl-induced apoptosis in HEK 293 cells. MEKKl-induced caspase 3-like protease activation is inhibited with expression of Akt. This inhibition by Akt prevents cleavage of endogenous MEKKI following exposure to etoposide and uV. Also, in an early signaling event, we show that MEKKl leads to activation of death receptor 4 (DR4) and death receptor 5 (DR5). Expression of either the decoy receptor 1 (DcRl) or FADD dominant negative protein (FADD DN) inhibits MEKKl-induced apoptosis. Akt, however, failed to block etoposide induced upregulation of DR4 and DRS expression and activation of caspase 8. In addition, Akt does not block MEKKl-induced JNK activation. Thus, we delineate that Akt inhibits MEKKl-induced apoptosis specifically through blocking caspase 3-like protease activation and amplification, resulting in inhibition of cleavage of MEKKl to its 91 kDa fragment.