A-Kinase Anchoring Protein (AKAP)-Lbc Anchors a PKN-based Signaling Complex Involved in α1-Adrenergic Receptor-induced p38 Activation

The mitogen-activated protein kinases (MAPKs) pathways are highly organized signaling systems that transduce extracellular signals into a variety of intracellular responses. In this context, it is currently poorly understood how kinases constituting these signaling cascades are assembled and activated in response to receptor stimulation to generate specific cellular responses. Here, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor activity, is critically involved in the activation of the p38 alpha MAPK downstream of alpha(1b)-adrenergic receptors (alpha(1b)-ARs). Our results indicate that AKAP-Lbc can assemble a novel transduction complex containing the RhoA effector PKN alpha, MLTK, MKK3, and p38 alpha, which integrates signals from alpha(1b)-ARs to promote RhoA-dependent activation of p38 alpha. In particular, silencing of AKAP-Lbc expression or disrupting the formation of the AKAP-Lbc.p38 alpha signaling complex specifically reduces alpha(1)-AR-mediated p38 alpha activation without affecting receptor-mediated activation of other MAPK pathways. These findings provide a novel mechanistic hypothesis explaining how assembly of macromolecular complexes can specify MAPK signaling downstream of alpha(1)-ARs.