Active and Inactive Protein Kinases: Structural Basis for Regulation

Johnson, L.N.; Noble, M.E.M.; Owen, David J.

doi:10.1016/s0092-8674(00)81092-2

Cited by 1,298 publications

(1,233 citation statements)

References 37 publications

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“…All protein kinases possess an aspartic acid residue in subdomain VIb which is believed to be important as a catalytic base. Kinases that are known to be activated by phosphorylation, in general, possess a basic residue immediately preceding the catalytic aspartate (arginine\aspartate kinases) [39]. It has been suggested that RD kinases require neutralization of this basic residue by the incorporated phosphate to obtain the active conformation.…”

Section: Discussionmentioning

confidence: 99%

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

Collins

Reoma

Gamm

et al. 2000

Biochemical Journal

164

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Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by melanocytic macules, hamartomatous polyps and an increased risk for numerous cancers. The human LKB1 (hLKB1) gene encodes a serine/threonine protein kinase that is deficient in the majority of patients with PJS. The murine LKB1 (mLKB1) cDNA was isolated, sequenced and shown to produce a 2.4-kb transcript encoding a 436 amino acid protein with 90% identity with hLKB1. RNA blot and RNase-protection analysis revealed that mLKB1 mRNA is expressed in all tissues and cell lines examined. The widespread expression of LKB1 transcripts is consistent with the elevated risk of multiple cancer types in PJS patients. The predicted LKB1 protein sequence terminates with a conserved prenylation motif (Cys433-Lys-Gln-Gln436) directly downstream from a consensus cAMP-dependent protein kinase (PKA) phosphorylation site (Arg428-Arg-Leu-Ser431). The expression of enhanced green fluorescent protein (EGFP)-mLKB1 chimaeras demonstrated that LKB1 possesses a functional prenylation motif that is capable of targeting EGFP to cellular membranes. Mutation of Cys433 to an alanine residue, but not phosphorylation by PKA, blocked membrane localization. These findings suggest that PKA does phosphorylate LKB1, although this phosphorylation does not alter the cellular localization of LKB1.

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Section: Discussionmentioning

confidence: 99%

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

Collins

Reoma

Gamm

et al. 2000

Biochemical Journal

164

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“…Kinase activation in general is dependent upon the A or activating loop moving from an inactive to active conformation in order to uncover the kinase active site and to orientate key amino acids which catalyse substrate phosphorylation (see Johnson et al, 1996). Recently, mutations of c-fms and the closely related proto-oncogene c-kit have been identi®ed that change equivalent aspartate residues to valine within the activating loops of the M-CSF and SCF receptors.…”

Section: Introductionmentioning

confidence: 99%

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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“…It is known that the A-loop must undergo a large change in conformation for kinase activation to occur (Johnson et al, 1996). Consequently, it is suggested that downregulation of the M-CSF receptor and of tyrosine kinase receptors in general is normally initiated by some aspect or consequence of the change in conformation of the A-loop that is induced by ligand-binding.…”

Section: Discussionmentioning

confidence: 99%

Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity

1999

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The downregulation of tyrosine kinase receptors attenuates signalling and is thought to be dependent upon intrinsic receptor kinase activity, largely because downregulation is inhibited by a kinase-inactivating mutation of an invariant lysine residue of the receptors for EGF, insulin, M-CSF and PDGF. We con®rmed that this mutation inhibited the degradation of the M-CSF receptor. However, two di erent kinase inactivating mutations of the invariant amino acids Gly 591 and Glu 633 did not prevent M-CSF-induced receptor degradation, so demonstrating that receptor kinase activity is not essential for this process. Three other kinase-inactivating mutations were found to cause constitutive receptor degradation in the absence of M-CSF, most probably by disrupting the structure of the activating loop of the kinase domain. It is known that extensive movement of the A-loop is necessary for kinase activation and is normally induced by ligand-binding. It is therefore suggested that some aspect or consequence of the change in structure of the A-loop caused by ligand binding also activates receptor downregulation, so ensuring that downregulation is coupled to but is not necessarily dependent upon receptor kinase activity.

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Active and Inactive Protein Kinases: Structural Basis for Regulation

Cited by 1,298 publications

References 37 publications

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

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

Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity

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