title: A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in α1-adrenergic receptor-induced p38 activation.
abstract: 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 p38α MAPK downstream of α(1b)-adrenergic receptors (α(1b)-ARs). Our results indicate that AKAP-Lbc can assemble a novel transduction complex containing the RhoA effector PKNα, MLTK, MKK3, and p38α, which integrates signals from α(1b)-ARs to promote RhoA-dependent activation of p38α. In particular, silencing of AKAP-Lbc expression or disrupting the formation of the AKAP-Lbc·p38α signaling complex specifically reduces α(1)-AR-mediated p38α 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 α(1)-ARs.
authors.affiliation: From the Département de Pharmacologie et de Toxicologie, Faculté de Biologie et Médecine, University of Lausanne, Lausanne 1005, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Cariolato
authors.affiliation: From the Département de Pharmacologie et de Toxicologie, Faculté de Biologie et Médecine, University of Lausanne, Lausanne 1005, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cavin
authors.affiliation: From the Département de Pharmacologie et de Toxicologie, Faculté de Biologie et Médecine, University of Lausanne, Lausanne 1005, Switzerland. Electronic address: Dario.diviani@unil.ch.
authors.forename: Dario
authors.initials: D
authors.lastname: Diviani
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D018340:Receptors, Adrenergic, alpha-1; C066737:RHOA protein, human; C061570:protein kinase N; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein