Activation-Loop Autophosphorylation Is Mediated by a Novel Transitional Intermediate Form of DYRKs

Lochhead, Pamela A.; Sibbet, Gary; Morrice, Nick; Cleghon, Vaughn

doi:10.1016/j.cell.2005.03.034

Cited by 282 publications

(336 citation statements)

References 43 publications

Supporting

Mentioning

315

Contrasting

Unclassified

Order By: Relevance

“…6 However, to achieve full kinase activity, one fully conserved tyrosine (Tyr 321) in the activation loop must be constitutively autophosphorylated immediately after translation. 25 E2F1, FOXO1, GLI1, GSK3, INI1/SNF5, NFAT, RAS, RAF, MEK1, SRSF6, STAT3, SJI1, and SIRT1. 5 The overexpression of DYRK1A affects the expression of 239 genes through the NRSF/REST-SWI/SNF chromatin-remodeling complex, a key regulator of pluripotency and neuronal differentiation, indicating an essential role of this kinase in cell cycle and in brain development.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

View full text Add to dashboard Cite

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

show abstract

Section: Discussionmentioning

confidence: 99%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The Drosophila DYRKs, minibrain (MNB) and dDyrk2, autophosphorylate on tyrosine intramolecularly while the polypeptide is still bound to ribosomes [13]. After translation, the mature kinase appears to lose tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

View full text Add to dashboard Cite

The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosinephosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. Structured digital abstract• CLK1 and CLK1 phosphorylate by protein kinase assay (View interaction)• HIPK2 and HIPK2 phosphorylate by protein kinase assay (View interaction)• DYRK1A phosphorylates SF3B1 by protein kinase assay (View interaction)• DYRK1A and DYRK1A phosphorylate by protein kinase assay (View interaction)

show abstract

“…For some kinases, however, such a distinction cannot be made so clearly. For example, several predominantly Ser/Thr kinases have been shown to also (auto)phosphorylate Tyr residues 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. The inverse, a Tyr kinase that also (auto)phosphorylates on Ser/Thr residues, is less common, but occurring nonetheless 20, 21.…”

mentioning

confidence: 99%

“…The inverse, a Tyr kinase that also (auto)phosphorylates on Ser/Thr residues, is less common, but occurring nonetheless 20, 21. The role of this ‘dual specificity’ is well‐described for some kinases 9, 10, 18, 19. Other (auto)phosphorylation events are less well understood in terms of function, and sometimes dual specificity is only seen under specific circumstances 19.…”

mentioning

confidence: 99%

“…The role of this ‘dual specificity’ is well‐described for some kinases 9, 10, 18, 19. Other (auto)phosphorylation events are less well understood in terms of function, and sometimes dual specificity is only seen under specific circumstances 19. While it is known that some kinases have a dual specificity, the molecular determinants in kinases that confer to this property have not been examined in close detail.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation

et al. 2018

View full text Add to dashboard Cite

The protein kinase D (PKD) family is regulated through multi‐site phosphorylation, including autophosphorylation. For example, PKD displays in vivo autophosphorylation on Ser‐742 (and Ser‐738 in vitro) in the activation loop and Ser‐910 in the C‐tail (hPKD1 numbering). In this paper, we describe the surprising observation that PKD also displays in vitro autocatalytic activity towards a Tyr residue in the P + 1 loop of the activation segment. We define the molecular determinants for this unusual activity and identify a Cys residue (C705 in PKD1) in the catalytic loop as of utmost importance. In cells, PKD Tyr autophosphorylation is suppressed through the association of an inhibitory factor. Our findings provide important novel insights into PKD (auto)regulation.

show abstract

Activation-Loop Autophosphorylation Is Mediated by a Novel Transitional Intermediate Form of DYRKs

Cited by 282 publications

References 43 publications

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

Mechanism of dual specificity kinase activity of DYRK1A

Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation

Contact Info

Product

Resources

About