A conserved helix motif complements the protein kinase core.

Véron, Michel; Radzio‐Andzelm, Elzbieta; Tsigelny, Igor F.; Eyck, Lynn F. Ten; Taylor, Susan S.

doi:10.1073/pnas.90.22.10618

Cited by 77 publications

(64 citation statements)

References 35 publications

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“…The A helix of cAMP dependent protein kinase (cAPK) interacts with and stabilizes the active form of the activating loop (Veron et al, 1993). In the active state, Arg190 of the activating loop of cAPK makes van der Waals contact with two hydrophobic amino acids of the A helix, Phe26 and the invariant Trp30 (Veron et al, 1993).…”

Section: Mechanism Of Receptor Activationmentioning

confidence: 99%

“…In the active state, Arg190 of the activating loop of cAPK makes van der Waals contact with two hydrophobic amino acids of the A helix, Phe26 and the invariant Trp30 (Veron et al, 1993). Asp802 of the M-CSF receptor is equivalent to Arg190 of cAPK which raises the possibility that Asp802 interacts with the hydrophobic amino acids Tyr571 and Trp575 of the A helix of the Asp 802 is in a region of the M-CSF receptor that corresponds to the 5 amino acid aL12 helix within the activating loop of inactive cyclin-dependent kinase CDK-2.…”

Section: Mechanism Of Receptor Activationmentioning

confidence: 99%

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Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

et al. 1999

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Expression of a receptor for human macrophage-colony stimulating factor (M-CSF or CSF-1), containing a point mutation which changes an aspartate to a valine at position 802 of the activating loop of the kinase domain, potently transforms the haemopoietic cell line FDC-P1 yet prevents Rat-2 ®broblast transformation. In order to understand this apparent paradox, aspartate 802 was changed by cassette mutagenesis to each of the other 19 amino acids. All hydrophobic amino acid substitutions were transforming when tested in FDC-P1 cells yet inactivating when tested in Rat-2 ®broblasts. These same amino acid substitutions also activated receptor degradation, strongly suggesting a causal relationship between receptor degradation and inactivation in ®broblasts. Point mutations or small deletions of Y708 within the kinase insert region of the mutant D802V receptor partly inhibited receptor degradation. The more stable D802V receptor derivatives were able to transform both FDC-P1 cells and Rat-2 ®broblasts, so establishing that the cell speci®c e ect of the c-fmsD802V activating loop mutation is attributable to receptor degradation which accompanies kinase activation and prevents the transformation of Rat-2 but not of FDC-P1 cells.

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Section: Mechanism Of Receptor Activationmentioning

confidence: 99%

Section: Mechanism Of Receptor Activationmentioning

confidence: 99%

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

et al. 1999

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“…Pim-1 is a small 35-kDa protein that consists of a catalytic domain without obvious autoregulatory or association domains, but it may still complex with other proteins. An imperfect amphipathic ␣-helix motif in the COOH terminus of Pim-1, similar to that of cAMP-dependent protein kinase (57) and as of yet without a defined function, could be involved in regulatory protein-protein interactions. Alternatively, phosphorylation of Pim-1 at its NH 2 terminus may also regulate the kinase indirectly.…”

Section: Pim-1 Kinase Autophosphorylationmentioning

confidence: 99%

Identification of the Autophosphorylation Sites of theXenopus laevis Pim-1 Proto-oncogene-encoded Protein Kinase

Palaty

Kalmar

Tai

et al. 1997

Journal of Biological Chemistry

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Pim-1 is an oncogene-encoded serine/threonine kinase expressed primarily in cells of the hematopoietic and germ line lineages. Previously identified only in mammals, pim-1 cDNA was cloned and sequenced from the African clawed frog Xenopus laevis. The coding region of Xenopus pim-1 encoded a protein of 324 residues, which exhibited 64% amino acid identity with the full-length human cognate. Xenopus Pim-1 was expressed in bacteria as a glutathione S-transferase (GST) fusion protein and in COS cells. Phosphoamino acid analysis revealed that recombinant Pim-1 autophosphorylated on serine and threonine and to a more limited extent on tyrosine. Electrospray ionization mass spectroscopy was undertaken to locate these phosphorylation sites, and the primary autophosphorylation site of GST-Pim-1 was identified as Ser-190 with Thr-205 and Ser-4 being minor sites. Ser-190, which immediately follows the high conserved Asp-Phe-Gly motif in catalytic subdomain VII, is also featured in more than 20 other protein kinases. To evaluate the importance of the Ser-190 site on the phosphotransferase activity of Pim-1, Ser-190 was mutated to either alanine or glutamic acid, and the constructs were expressed in bacteria as GST fusion proteins and in COS cells. These mutants confirmed that Ser-190 is a major autophosphorylation site of Pim-1 and indicated that phosphorylation of Pim-1 on the Ser-190 residue may serve to activate this kinase.

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“…Phosphorylations, or interactions with other proteins, that relax autoinhibition, are required for the activation of these enzymes. For example, the activation of MAPKAPK2, in addition to phosphorylation of Thr 205 in the catalytic site, correlated with phosphorylation of a threonine in a PXTP 318 motif in the C-terminal tail, which contains an autoinhibitory domain with homology to the amphiphilic A-helix of other kinases (22)(23)(24). In CaMKII, a C-terminal segment blocks the catalytic site in the absence of calmodulin; upon calmodulin binding, a threonine within that segment is phosphorylated, disrupting autoinhibition and leading to a calcium-independent active state of the enzyme (25, 26).…”

mentioning

confidence: 99%

C-terminal Elements Control Location, Activation Threshold, and p38 Docking of Ribosomal S6 Kinase B (RSKB)

Tomás-Zuber¹,

Mary²,

Lamour³

et al. 2001

Journal of Biological Chemistry

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RSKB, a p90 ribosomal S6 protein kinase with two catalytic domains, is activated by p38-and extracellular signal-regulated kinase mitogen-activated protein kinase pathways. The sequences between the two catalytic domains and of the C-terminal extension contain elements that control RSKB activity. The C-terminal extension of RSKB presents a putative bipartite 713 KRX 14 KRRKQKLRS 737 nuclear location signal. The distinct cytoplasmic and nuclear locations of various C-terminal truncation mutants supported the hypothesis that the nuclear location signal was essential to direct RSKB to the nuclear compartment. The 725 APLA-KRRKQKLRS 737 sequence also was essential for the intermolecular association of RSKB with p38. The activation of RSKB through p38 could be dissociated from p38 docking, because RSKB truncated at Ser 681 strongly responded to p38 pathway activity. Interestingly, ⌬ 725-772 -RSKB was nearly nonresponsive to p38. Sequence alignment with the autoinhibitory C-terminal extension of Ca ؉2 /calmodulin-dependent protein kinase I predicted a conserved regulatory 708 AFN 710 motif. Alanine mutation of the key Phe 709 residue resulted in strongly elevated basal level RSKB activity. A regulatory role also was assigned to Thr 687 , which is located in a mitogen-activated protein kinase phosphorylation consensus site. These findings support that the RSKB C-terminal extension contains elements that control activation threshold, subcellular location, and p38 docking.The p90 ribosomal S6 protein kinases (RSKs) 1 are a family of Ser/Thr protein kinases composed of two catalytic domains, each with canonical ATP-binding site and activation loop sequences. In addition, RSKs contain a regulatory linker sequence connecting the two kinase domains and an extended C-terminal tail. RSKs comprise RSK1-RSK3, which are stimulated through the ERK pathway (1-6); the more recently identified mitogen-and stress-activated protein kinase type 1 and RSKB, which are activated by both the p38 and ERK pathways (7-9); and RSK4 (10). RSKs are involved in many diverse functions, such as regulation of glycogen metabolism by phosphorylating glycogen synthase kinase-3 and the G-subunit of protein phosphatase 1, and cell survival of cerebellar neurons through phosphorylation of BAD (reviewed in Refs. 11-13). RSKs function in the control of M phase entry of oocytes during meiosis and chromatin remodeling through histone H3 phosphorylation (14, 15). Furthermore, RSKs participate in the regulation of transcription factors and coregulators, such as CREB (3-5, 7, 8), CREB-binding protein and p300 (16), c-Fos (17), and estrogen receptor (18). Deficient mutants of RSK2 in man are linked to Coffin-Lowry syndrome, characterized by mental retardation and malformations (19). Deletion of RSK4 is common in patients with X-linked mental retardation (10). Interestingly, RSKB maps to the BBS1 locus (20), which is associated with Bardet-Biedl syndrome with manifestations reminiscent of Coffin-Lowry syndrome (21), and may be a candidate BBS gene.Many Ser/Thr-ki...

show abstract

A conserved helix motif complements the protein kinase core.

Cited by 77 publications

References 35 publications

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

Identification of the Autophosphorylation Sites of theXenopus laevis Pim-1 Proto-oncogene-encoded Protein Kinase

C-terminal Elements Control Location, Activation Threshold, and p38 Docking of Ribosomal S6 Kinase B (RSKB)

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