MAP2K2

Abstract: The development and life-time of multicellular eukaryotic organisms represents a complex interplay of numerous proliferation and differentiation events that proceed in a highly ordered manner. As a prerequisite for those events, cells must respond to extracellular signals with a specific set of mechanisms that regulate or modulate gene expression. Between the signal and the gene, a system of rather different cellular components is assembled to guarantee a specific and successful process of signal transduction. Pathways of signal transduction, though differing remarkably in their complexity and in the use of cellular components, seem to obey certain principles which are evolutionarily conserved and ubiquitously distributed amongst living organisms. Extracellular signals, so-called ligands, either penetrate the cellular membrane or bind to the extracellular domain of receptors. Activated receptors as such, or in association with socalled transducers, are capable of activating effectors-either directly or by means of changing the amount or intracellular distribution of so-called second messengers. These second

Abstract: Brassinosteroids (BRs) bind to the extracellular domain of the receptor kinase BRI1 to activate a signal transduction cascade that regulates nuclear gene expression and plant development. Many components of the BR signaling pathway have been identified and studied in detail. However, the substrate of BRI1 kinase that transduces the signal to downstream components remains unknown. Proteomic studies of plasma membrane proteins lead to the identification of three homologous BR-signaling kinases (BSK1, BSK2, and BSK3). The BSKs are phosphorylated by BRI1 in vitro and interact with BRI1 in vivo. Genetic and transgenic studies demonstrate that the BSKs represent a small family of kinases that activate BR signaling downstream of BRI1. These results demonstrate that BSKs are the substrates of BRI1 kinase that activate downstream BR signal transduction.

Abstract: Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.

Abstract: Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Over time, chemical discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling, and some have progressed from simple tool compounds into clinically validated therapeutics. This review explores several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been the finding of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP-binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase have been found. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets is discussed.