Systems Biology and Kinase Signaling

Contents 1. Complexity and Scope in Systems Kinase Biology 393 

An Example of the Practical Application of Systems Biology ErbB 

Systems Biology Group, Research Technology Center, Pfizer Inc., Cambridge, MA, USA 

Annual Reports in Medicinal Chemistry, Volume 42 2007 Elsevier Inc. 

Computational methods have been applied to determine the connections in systems that are not well-defined by canonical pathways. This is either done by semi-automated and/or curated literature causal modeling [1] or by statistical methods based on large-scale data from expression or proteomic studies (a mostly theoretical approach is given by reference [2] and a more applied approach is in reference [3]). Many methods, including clustering, Bayesian analysis and principal component analysis have been used to find relationships and fingerprints in gene expression data [4]. 

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The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

A property of the protein kinase C enzyme family that is highly valuable for their identification and characterization is their activation by tumor promoters such as phorbol esters (Fig. 7.7). Protein kinase C binds to the tumor promoter, tetradecanoyl phorbol acetate (TPA), with high affinity and is activated by this binding. The specific activation of protein kinase C by phorbol esters is an important tool to demonstrate their involvement in signal transduction pathways. By external addition of TPA, it is possible to use cellular model systems to test which biological responses of a signal transduction pathway involve, and are controlled by, protein kinase C. 

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