Protein kinase threonine

The last part of this account will be devoted to protein kinases and protein phosphatases and some recent results we have obtained for them. Protein kinases and phosphatases are signaling biomolecules that control the level of phosphorylation and dephosphorylation of tyrosine, serine or threonine residues in other proteins, and by this means regulate a variety of fundamental cellular processes including cell growth and proliferation, cell cycle and cytoskeletal integrity. 

Phosphorylation is a common method of regulation. As described above, SH2 domains bind to phosphorylated tyrosine residues. Conversely, phosphorylation of serines and threonines proximal to SH3 and PDZ domains uncouples them from their target motifs. Therefore modulation of protein kinase activity in cells regulates interactions between adaptor proteins and their target proteins. 

The a subunits, for which two isoforms exist in mammals (al, a2), contain conventional protein serine/threonine kinase domains at the N-terminus, with a threonine residue in the activation loop (Thr-172) that must be phosphorylated by upstream kinases (see below) before the kinase is active. The kinase domain is followed by an autoinhibitory domain, whose effect is somehow relieved by interaction with the other subunits. The C-terminal domain of the a subunit is required for the formation of a complex with the C-terminal domain of the (3 subunit, which in turn mediates binding to the y subunit. The al and a2 catalytic subunit isoforms are widely distributed, although a2 is most abundant in muscle and may be absent in cells of the endothelial/hemopoietic lineage. 

Serine/threonine protein kinase phosphorelay modules... 

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... 

The antisense oligonucleotide LErafAON against the serine/threonine kinase c-Raf has been tested in phase I clinical trials. The antisense oligonucleotides ISIS-5132, which also inhibits c-Raf, and ISIS-3521, which inhibits PKC, went through different phase clinical trials with solid tumour patients. Unfortunately, no objective responses occurred with these PKI. GEM-231, an oligonucleotide targeting the RIa subunit of protein kinase A is currently undergoing phase I/II clinical trials alone or in combination with traditional therapy for the treatment of solid cancers [3]. 

Raf kinases such as Rafl are serine/threonine-specific protein kinases which function in signal transduction... 

S6K1 (also known as p70S6 kinase) is a serine/ threonine protein kinase which is involved in the regulation of translation by phosphorylating the 40S ribosomal protein S6. Insulin and several growth factors activate the kinase by phosphorylation in a PI 3-kinase dependent and rapamycin-sensitive manner. Phosphorylation of S6 protein leads to the translation of mRNA with a characteristic 5 polypyrimidine sequence motif. 

PKR Double-stranded RNA-activated protein kinase A serine threonine kinase that phos-phorylates eIF2a on serine residue 51 when activated... 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

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. 

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