Protein phosphorylation cascades

Denhardt DT. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell the potential for multiplex signalling. B/oc/jeraJ 1996 318 729-747. 

P. Cohen. Dissection of the protein phosphorylation cascades involved in insulin and growth factor action. Biochem Soc Trans, 21, 555-567, 1993. 

The control of cellular proliferation and differentiation in response to external stimuli is achieved by signal transduction pathways, which are regulated in part by the co-ordinated action of protein kinases and phosphatases. In eukaryotic cells the protein kinases involved fall primarily into two classes, those that phosphorylate tyrosine residues and those that are specific for serine and threonine residues. Prokaryotic cells also rely on protein phosphorylation cascades for regulation of cellular activities, but the kinases involved are primarily histidine kinases, which are part of the sensing domain of two-component regulatory systems. These histidine kinases and their associated response regulators are involved in a range of adaptive responses by bacteria. 

TSH (also called thyrotropin), which is secreted by the pituitary, plays a central role in the regulation of growth and function of the thyroid gland. TSH receptors are functionally coupled to G-proteins thus, the extracellular stimulus by TSH is transduced into intracellular signals mediated by a number of G-proteins. Activation of Gs-protein results in the stimulation of the adenylate cyclase-cAMP-protein phosphorylation cascade. Other G-proteins coupled to TSH-receptor activation include Gg-protein, which mediates the phospholipase C-phosphatidylinositol 4,5-bisphosphate-Ca + signaling pathway (see Chapter 30 for a detailed discussion). 

Protein phosphorylation cascades are involved in multiple intracellular signaling pathways. 

Cascade In several situations in the body, a series of similar enzyme reactions occurs in which a signal is passed and often amplified between the beginning and end of the series. Such a series is called a cascade. The most common types are proteolytic and protein phosphorylation cascades. 

The next step in the transduction process is more problematical. On the one hand, evidence has been adduced indicating that the ETR protein interacts directly with the CTRl protein kinase [64], On the other hand the rapid effects of ethylene on the activation of SMG proteins suggests that these may play a role in linking the receptor to Raf or other protein phosphorylation cascades, as in the case in animals [65-68], The possible role of such proteins is in itself complex since they may not only control pathways separate from protein phosphorylation cascades (e.g. phosphoinositides [69,70] but may themselves interact via GTPase cascades [71]. Equally, it is important to mention that the small GTP-binding proteins constitute a superfamily, the various members of which may have very different functions [72-77]. In neither Arabidopsis [60] nor in peas [59] is it yet clear which member(s) of the superfamily are activated. 

Protein phosphorylation cascades, like the one discussed above, are a general mechanism of cellular regulation. Protein kinases are involved in the control of metabolism, gene expression, and cell growth, among other processes. 

Everley, P. A., Dillman III, J.F., 2010. A large-scale quantitative proteomic approach to identifying sulfur mustard-induced protein phosphorylation cascades. Chem. Res. Toxicol. 23, 20-25. 

The kinases themselves can be arranged into phosphorylation cascades so that one kinase phosphorylates another, which, in turn, phos-phorylates another. This often leads to some funny names, such as MAP kinase kinase kinase. This means a mitogen-activated protein kinase that phosphorylates MAP kinase kinase. The activated MAP kinase kinase then phosphorylates and activates MAP kinase. 

The PROTEIN KINASE CASCADE amplifies the original extracellular signal by increasing levels of cAMP, which activates cAMP-dependent protein kinase, which phosphorylates specific proteins. 

Several key questions remain with regard to the regulation of tyrosine hydroxylase by phosphorylation. What is the precise effect of the phosphorylation of each of these serine residues on the catalytic activity of the enzyme How does the phosphorylation of multiple residues affect enzyme activity Does the phosphorylation of one residue affect the ability of the others to be phosphorylated Tyrosine hydroxylase provides a striking example as to how multiple intracellular messengers and protein kinases converge functionally through the phosphorylation of a single substrate protein. Phosphorylation of tyrosine hydroxylase by cAMP-dependent and Ca2+-dependent protein kinases and by MAPK cascades... 

Cellular signals converge at the level of protein phosphorylation pathways. Individual intracellular messenger pathways, such as cAMP, Ca2+ and MAPK pathways, are often drawn as distinct biochemical cascades that operate in parallel in the control of cell function. While this is useful for didactic purposes, it is now well established that these various pathways function as complex webs, with virtually every conceivable type of interaction seen among them. 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

Ge Z, Liu C, Bjorkholm M, Gruber A, Xu D (2006) Mitogen-activated protein kinase cascade-mediated histone H3 phosphorylation is critical for telomerase reverse transcriptase expression/telomerase activation induced by proliferation. Mol Cell Biol 26(l) 230-237 Giet R, Glover DM (2001) Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 152(4) 669-682... 

Figure 21.9 The mitogen-activated protein kinase cascade (MAP kinase cascade). The active protein Ras activates Raf by promoting its recruitment to a cell membrane. Through a series of phosphorylations MAP kinase is activated as follows MAP kinase kinase kinase (Raf) phosphorylates MAP kinase kinase which, in turn, phosphorylates MAP kinase, the final target enzyme. MAP kinase phosphorylates transcription factors for genes that express proteins involved in proliferation. Another nomenclature for the enzymes is also used raf is MEKK MAPKK is MEK and finally ERK is MAP kinase (ERK is the abbreviation for extracellular-signal-related kinase) For comparison, the reader is referred to the metabolic phosphorylase cascade, which is discussed in Chapter 12 (Figure 12.12).

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