Kinase serine/threonine

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. 

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

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... 

PKC is a family of enzymes whose members play central roles in transducing information from external stimuli to cellular responses. Members of this family of serine/ threonine kinases respond to signals that cause lipid hydrolysis. PKC isozymes phosphorylate an abundance of substrates, leading to both short-term cellular responses such as regulation of membrane transport and long-term responses such as memory and learning. 

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]. 

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. 

Very large Serine/Threonine kinases and the molecular Target of Rapamycin, a naturally occurring secondary metabolite, TOR proteins function within multiprotein complexes to couple cell growth and stress responses to environmental and developmental cues. 

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

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

Polymorphism of the MC1R gene on chromosome 16 (16q24), which is associated with red hair, also increases susceptibility to melanoma.23 Mutations affecting the serine-threonine kinase B-RAF gene have been reported with high rates in individuals with MM.24 The RAF serine-threonine... 

Somatostatin (sstl—sst5) Nonreceptor serine/threonine kinases Elastase... 

Cytoplasmic serine/threonine protein kinases catalyze the transfer of phosphate groups to serine and threonine residues of target proteins. Serine/threonine kinases have been recognized as the products of protooncogenes (e.g., c-mos, c-raj) or as kinases intimately involved with the regulation of serine/threonine kinase activity by cAMP. Some of these kinases specifically phosphorylate cellular structural proteins, such as histone, laminins, etc. Others phosphorylate still more kinases, resulting in either the activation or deactivation of downstream protein kinases. Specific examples in which serine/threonine kinases elicit specific cellular responses are discussed in this chapter. 

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