How Tyrosine 15 Phosphorylation Inhibits the Activity of Cyclin-dependent Kinase 2-Cyclin A

Welburn, Julie; Tucker, J.A.; Johnson, Tim; Lindert, Lisa; Morgan, Rhodri M. L.; Willis, Antony C.; Noble, M.E.M.; Endicott, Jane

doi:10.1074/jbc.m609151200

Cited by 89 publications

(67 citation statements)

References 61 publications

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“…[33][34][35] However, to date, the mechanisms underlying the inhibition of CCND-dependent kinases by tyrosine phosphorylation have not been elucidated. Here we bring direct new evidences that phosphorylation of Y24 inhibits CDK6 activities by preventing its association with CCNDs.…”

Section: Discussionmentioning

confidence: 99%

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

et al. 2013

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Disruption of contact inhibition and serum afflux that occur after a tissue injury activate cell cycle, which then stops when confluence is reached again. Although the events involved in cell cycle entry have been widely documented, those managing cell cycle exit have remained so far ill defined. We have identified that the final stage of wound closure is preceded in keratinocytes by a strong accumulation of miR-483-3p, which acts as a mandatory signal triggering cell cycle arrest when confluence is reached. Blocking miR-483-3p accumulation strongly delays cell cycle exit, maintains cells into a proliferative state and retards their differentiation program. Using two models of cell cycle synchronization (i.e. mechanical injury and serum addition), we show that an ectopic upregulation of miR-483-3p blocks cell cycle progression in early G1 phase. This arrest results from a direct targeting of the CDC25A phosphatase by miR-483-3p, which can be impeded using an anti-miRNA against miR-483-3p or a protector that blocks the complex formation between miR-483-3p and the 3 0 -untranslated region (UTR) of CDC25A transcript. We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases' activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. We propose this new regulatory process of cyclin-CDK association as a general mechanism coupling miRNA-mediated CDC25A invalidation to CDK posttranscriptional modifications and cell cycle control.

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Section: Discussionmentioning

confidence: 99%

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

et al. 2013

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“…Indeed, cyclin-dependent protein kinases (CDKs) are regulated in part by inhibitory phosphorylation of conserved residues within the active site. Detailed studies with cyclin-dependent kinase 2 (CDK2) demonstrated that phosphorylation of threonine-14 and tyrosine-15 within the glycine-rich loop (GEGTYGVVY) inhibits kinase activity by interfering with peptide substrate binding and alters, but does not prevent, ATP binding (32). With the CDKs, the inhibitory phosphorylation within the ATP-binding domain is catalyzed by other kinases, whereas with BRI1 the inhibitory modification is an autophosphorylation reaction.…”

Section: Discussionmentioning

confidence: 99%

Deactivation of the Arabidopsis BRASSINOSTEROID INSENSITIVE 1 (BRI1) receptor kinase by autophosphorylation within the glycine-rich loop

Wang

Clouse

2011

Proc. Natl. Acad. Sci. U.S.A.

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The activity of the dual-specificity receptor kinase, brassinosteroid insensitive 1 (BRI1), reflects the balance between phosphorylationdependent activation and several potential mechanisms for deactivation of the receptor. In the present report, we elucidate a unique mechanism for deactivation that involves autophosphorylation of serine-891 in the ATP-binding domain. Serine-891 was identified previously as a potential site of autophosphorylation by mass spectrometry, and sequence-specific antibodies and mutagenesis studies now unambiguously establish phosphorylation of this residue. In vivo, phosphorylation of serine-891 increased slowly with time following application of brassinolide (BL) to Arabidopsis seedlings, whereas phosphorylation of threonine residues increased rapidly and then remained constant. Transgenic plants expressing the BRI1(S891A)-Flag-directed mutant have increased hypocotyl and petiole lengths, relative to wild-type BRI1-Flag (both in the bri1-5 background), and accumulate higher levels of the unphosphorylated form of the BES1 transcription factor in response to exogenous BL. In contrast, plants expressing the phosphomimetic S891D-directed mutant are severely dwarfed and do not accumulate unphosphorylated BES1 in response to BL. Collectively, these results suggest that autophosphorylation of serine-891 is one of the deactivation mechanisms that inhibit BRI1 activity and BR signaling in vivo. Many arginine-aspartate (RD)-type leucine-rich repeat receptor-like kinases have a phosphorylatable residue within the ATP-binding domain, suggesting that this mechanism may play a broad role in receptor kinase deactivation.T he receptor-like kinase (RLK) family in Arabidopsis contains more than 600 members, of which more than 400 are structurally and functionally similar to animal receptor kinases but are evolutionarily distinct (1). Animal receptor kinases are predominantly tyrosine kinases, whereas plant receptor kinases are generally classified as Ser/Thr kinases, although recent work suggests that some plant receptor kinases are dual-specificity kinases that can also autophosphorylate on tyrosine residues (2-5). One of the best-studied plant receptor kinases is BRASSINOSTEROID INSENSITIVE 1 (BRI1), which functions with its coreceptor, BRI1-ASSOCIATED RECEPTOR KINASE 1 (BAK1), in brassinosteroid (BR) signaling (6-11). Current thinking is that BRI1 and BAK1 are in their unphosphorylated forms and inactive in the absence of BR, whereas in the presence of the BR ligand, BRI1 and BAK1 heterodimerize and become activated via auto-and transphosphorylation (12). The BRI1 KINASE INHIBITOR 1 (BKI1) and the BR-signaling kinase 1 (BSK1) may be two of the immediate downstream components that are first phosphorylated by BRI1 (13,14). BSK then activates the BRI1 SUPPRESSOR 1 (BSU1) phosphatase (15), which in turn inhibits the glycogen synthase 3-like protein kinase, BRASSINOSTEROID INSENSITIVE 2 (BIN2), by dephosphorylation of an essential phosphotyrosine residue (16). The net result is that the transcription fac...

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“…Consistent with the above mutant description, we found dramatically reduced CDKA;1 activity in kinase assays of DE plants ( Figure 6C). Recently, Tyr-15 phosphorylation of Cdk2 has been shown to result in reduced substrate binding of the kinase (Welburn et al, 2007). Indeed, the interaction of DE with a bona fide CDK substrate (i.e., CDC6) was reduced when compared with that of the wild-type CDKA;1 (Figures 7A and 7B).…”

Section: Online)mentioning

confidence: 96%

Control of Cell Proliferation, Organ Growth, and DNA Damage Response Operate Independently of Dephosphorylation of the Arabidopsis Cdk1 Homolog CDKA;1

et al. 2009

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Entry into mitosis is universally controlled by cyclin-dependent kinases (CDKs). A key regulatory event in metazoans and fission yeast is CDK activation by the removal of inhibitory phosphate groups in the ATP binding pocket catalyzed by Cdc25 phosphatases. In contrast with other multicellular organisms, we show here that in the flowering plant Arabidopsis thaliana, cell cycle control does not depend on sudden changes in the phosphorylation pattern of the PSTAIRE-containing Cdk1 homolog CDKA;1. Consistently, we found that neither mutants in a previously identified CDC25 candidate gene nor plants in which it is overexpressed display cell cycle defects. Inhibitory phosphorylation of CDKs is also the key event in metazoans to arrest cell cycle progression upon DNA damage. However, we show here that the DNA damage checkpoint in Arabidopsis can also operate independently of the phosphorylation of CDKA;1. These observations reveal a surprising degree of divergence in the circuitry of highly conserved core cell cycle regulators in multicellular organisms. Based on biomathematical simulations, we propose a plant-specific model of how progression through the cell cycle could be wired in Arabidopsis.

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How Tyrosine 15 Phosphorylation Inhibits the Activity of Cyclin-dependent Kinase 2-Cyclin A

Cited by 89 publications

References 61 publications

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

Deactivation of the Arabidopsis BRASSINOSTEROID INSENSITIVE 1 (BRI1) receptor kinase by autophosphorylation within the glycine-rich loop

Control of Cell Proliferation, Organ Growth, and DNA Damage Response Operate Independently of Dephosphorylation of the Arabidopsis Cdk1 Homolog CDKA;1

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