Kinases kinase

MAP kinase signaling modules typically comprise a cassette of three protein kinases (Fig. 7.2A). For example, ERK (two isoforms in mammalian cells, ERK1/2) is phosphorylated (at Thr and Tyr residues in the activation loop of its catalytic domain by an upstream MAP kinase kinase (in this case, MEK) which is, in turn, phosphorylated and activated by a MAP kinase kinase kinase, in this instance, a member of the Raf group) (Fig. 7.2A). 

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. 

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

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).

Gilmore PM, McCabe N, Quinn JE et al. BRCA 1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3. Cancer Res 2004 64 4148 154. 

MAPKKK = Mitogen-activated Protein Kinase Kinase Kinase... 

A MAP kinase module is composed of three kinases where MAP kinase kinase kinase (MAPKKK) will phosphorylate and induce a MAP kinase kinase (MAPKK), which will then phosphorylate and activate a MAP kinase. MAP kinase phosphory-lates either transcription factors that are nonkinase proteins or other kinases that are called MAP kinase-activating protein kinases (MK). There are four distinct classes of MAP kinases, which include ERKs, C-Jun-N-terminal kinases, p38 isoforms and ERK5. 

Chadee DN, Yuasa T, Kyriakis JM. 2002. Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol. 22 737-749. 

Symons A, Beinke S, Ley SC. 2006. MAP kinase kinase kinases and innate immunity. Trends Immunol. 27 40-48. 

Liao, D.F., Duff, J.L., Daum, G., Pelech, S.L., and Berk, B.C. 1996. Angiotensin II stimulates MAP kinase kinase kinase activity in vascular smooth muscle cells. Role of Raf. Circ Res 79 1007-1014. 

Leung IW-L, Lassam N. 1998. Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. J Biol Chem... 

MAPKKK, MAPK kinase kinase, mitogen activated protein kinase kinase kinase MARGKS, myristoylated alanine-rich C kinase substrate... 

The phosphorylation cascade consists of a sequence of kinases, starting with MAPKKKs, (MAP kinase kinase kinases) followed by MAPKKs (MAP kinase kinases), and ending with MAPKs (MAP kinases). 

Yes tyrosine kinase Nuclear tyrosine phosphatase p65 Protein phosphatase 2A Phosphatase 2A inhibitor protein Rho-GDP-dissociation factor MAP kinase kinase kinase 8 GSK-3P... 

Manganese defuHenev. 803 Mannuronic acid, fP MAP kinase kinase kinase, 900 MAP kinase signaling pathway, 9tX)-901 Maple svrup urine disea.se. thiamine in, 608 ... 

Mitogen-activated protein kinase kinase kinase... 

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