Kinases serine/threonine/ tyrosine

Kosako, H Gotoh, Y Matsuda, S Ishikawa, M and Nishida, E. (1992). Xenopus MAP kinase activator is a serine/threonine/tyrosine kinase activated by threonine phosphorylation. EMBO J. 11 2903-2908. 

One of the most widespread modifications is phosphorylation or dephosphorylation of various amino acid side chains (e.g., serine, threonine, tyrosine, and histidine). These kinds of modification are most often a part of complex regulatory pathways, frequently under hormonal control. (See kinase cascade). 

Enzyme tyrosine kinases, serine/threonine kinases... 

Tyrosine phosphorylated IRS interacts with and activates PI 3-kinase [3]. Binding takes place via the SRC homology 2 (SH2) domain of the PI 3-kinase regulatory subunit. The resulting complex consisting of INSR, IRS, and PI 3-kinase facilitates interaction of the activated PI 3-kinase catalytic subunit with the phospholipid substrates in the plasma membrane. Generation of PI 3-phosphates in the plasma membrane reemits phospholipid dependent kinases (PDKl and PDK2) which subsequently phosphorylate and activate the serine/threonine kinase Akt (synonym protein... 

MAPK cascades are composed of three cytoplasmic kinases, the MAPKKK, MAPKK, and MAPK, that are regulated by phosphorylation (Fig. 1) [1, 2]. The MAPKKK, also called MEKK for MEK kinase, is a serine/threonine kinase. Selective activation of MAPKKKs by upstream cellular stimuli results in the phosphorylation of MAPKK, also called MEK for MAP/ERK kinase by the MAPKKK. MAPKKK members are structurally diverse and are differentially regulated by specific upstream stimuli. The MAPKK is phosphorylated by the MAPKKK on two specific serine/ threonine residues in its activation loop. The MAPKK family members are dual specificity kinases capable of phosphorylating critical threonine and tyrosine residues in the activation loop of the MAPKs. MAPKKs have the fewest members in the MAPK signaling module. MAPKs are a family of serine/threonine kinases that upon activation by their respective MAPKKs, are capable of phosphorylating cytoplasmic substrates as well as... 

After their synthesis (translation), most proteins go through a maturation process, called post-translational modification that affects their activity. One common post-translational modification of proteins is phosphorylation. Two functional classes of enzymes mediate this reversible process protein kinases add phosphate groups to hydroxyl groups of serine, threonine and tyrosine in their substrate, while protein phosphatases remove phosphate groups. The phosphate-linking... 

PTEN is a phosphatase, which is a product of a tumor suppressor gene. This phosphatase has an unusual broad specificity and can remove phosphate groups attached to serine, threonine, and tyrosine residues. It is believed that its ability to dephosphorylate phosphati-dylinositol (PI) 3,4,5-triphosphate, the product of PI-3 kinase, is responsible for its tumor suppressor effects. 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

Receptor Serine/Threonine Kinases Receptor Subtype Receptor Tyrosine Kinases Receptors... 

HAGIWARA M, INOUE s, TANAKA T, NUNOKI K, ITO M and HiDAKA H (1988) Differen-tial effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases Biochemical Pharmacology 37, 2987-92. 

Kinases are enzymes that place a phosphate group on a serine/threonine or a tyrosine residue of a protein or peptide. All kinase reactions use ATP as the phosphate source. Therefore there have been assays developed that monitor the loss or gain of the peptide/protein substrate (LANCE, ULight) [23], the loss of ATP (easylite luminescence kinaseGlo, Perkin Elmer) [20], or the gain of ADP (Tran-screener TR-FRET) [24]. Many of these formats are applicable to cell based assays. 

This intermediate MAPK activator (MAPK kinase, MAPKK) is a 45 kDa phosphoprotein capable of phosphorylating MAPK on serine/threonine and tyrosine residues (Matsuda et al., 1992 Nakielny et al., 1992a Kosako et al., 1993). Like MAPK, the activity of MAPKK is regulated by phosphorylation. During oocyte maturation MAPKK is phosphorylated on threonine residues (Kosako et al., 1992), and this phosphorylation is required for its activity (Ahn et al., 1991 Gomez and Cohen, 1991 Kosako et al., 1992 Matsuda et al., 1992). MPF can activate both MAPKK and MAPK in vitro, with the activation of MAPK lagging behind that of MAPKK however, MPF cannot activate either purified MAPKK or MAPK that has been dephosphorylated by phosphatases (Matsuda et al., 1992). MAPKK and MAPK are therefore believed to function downstream of MPF (Fig. 3). 

Figure 3. MAP kinase regulatory pathway. The MAP kinase signaling pathway begins with activation of the receptor tyrosine kinase (RTK) by exogenous signals, such as growth factors and insulin. The signal is then transmitted into the cell via activation of the Raf serine/threonine kinase either directly by the RTK or through the GTP-binding protein, Ras. The signal is then transmitted to the nucleus and to other cytoplasmic proteins via MAPKK and MAPK.

A murine male germ cell-assocated kinase (mak) was isolated by virtue of its weak homology to the v-ros tyrosine kinase (Matsushime et al., 1990). Although it was isolated because of its homology to a tyrosine kinase, sequence analysis revealed that it belongs to the serine/threonine... 

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