Regulatory Cascades

Glycogen phosporylase b kinase (also called synthase-phosphorylase kinase (SPK) or simply phosphorylase b kinase) is part of the glycogen kinase cascade regulatory system (Figure 13.18). The enzyme is converted from the inactive form to active by phosphorylation catalyzed by cAMP-dependent protein kinase. Glycogen phosphorylase b kinase, when active, phosphorylates the glycogen phosphorylase b (less active form) to convert it to the more active form (glycogen phosphorylase a). 

The hypothesis of a cascading regulatory mechanism is currently being revised. The originators of this hypothesis are attempting to take into account all the com-... 

VEGFs, the angiopoietins, the Ephrins and Notch molecules stand out as they act specifically or preferentially on the vascular system and have, thus, to be considered as key regulatory molecules of the angiogenic cascade [3]. 

Cottesman S (1996) Roles for energy-dependent proteases in regulatory cascades. In Lin ECC, Lynch AS (eds) Regidation of gene expression in Escherichia coli. R.G. Landes Co., Austin, TX, p 503... 

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

Nucleotides participate in reactions that fulfill physiologic functions as diverse as protein synthesis, nucleic acid synthesis, regulatory cascades, and signal transduction pathways. 

Once vesicles detach from the cytoskeleton they are free to participate in the release process but our understanding of precisely how this is brought about is still sketchy, despite the wealth of information which has accumulated over recent years. What is clear is that it involves a complex cascade of regulatory processes focusing on proteins bound to vesicle membranes, the axolemma and some cytoplasmic factors (see Calakos... 

A number of alternative sizing methods are available, and these are described in Table 8. The American Association of Pharmaceutical Scientists, Inhalation Focus Group conducted a comprehensive review of available methods, which was published in a series of articles identified in the last column of the table. All of the methods described either have been or are currently employed in the development of aerosol products. However, at this time only the inertial samplers, cascade impactors and impingers appear in compendial standards and in regulatory guidelines [44-46], Other methods such as thermal imaging are also under development and may give complementary size information to the current methods. 

Lamb, T. D. and Pugh, Jr., E. N., G-protein cascades gains and kinetics, Trends Neurosci., 15, 291-299, 1992. Rodbell, M., The role of hormone receptors and GTP-regulatory proteins in membrane transduction, Nature, 284, 17-22, 1974. 

Phosphoryl group transfer reactions add or remove phosphoryl groups to or from cellular metabolites and macromolecules, and play a major role in biochemistry. Phosphoryl transfer is the most common enzymatic function coded by the yeast genome and, in addition to its importance in intermediary metabolism (see Chapter 5), the reaction is catalysed by a large number of central regulatory enzymes that are often part of signalling cascades, such as protein kinases, protein phosphatases, ATPases and GTPases. 

Cyclic AMP diffuses away from the membrane and engages its own target which is an inactive protein kinase, called cAMP dependent protein kinase or protein kinase A (PKA). The inactive PKA is a tetramer of two catalytic subunits and two regulatory subunits. Binding of cAMP to the regulatory subunits causes structural changes and the two regulatory subunits dissociate from the two catalytic sub-units. The now activated protein kinase A, that is the C subunit dimer, initiates a downstream cascade by... 

---