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#kinase

12 public questions tagged with this topic.

amphibian -ll

GSK-3 normally functions by:

In resting cells GSK-3 beta resides in destruction complex with scaffold Axin and tumor suppressor APC, phosphorylating N-terminal residues Ser33, Ser37, Thr41 of beta-catenin. Phosphorylated beta-catenin recognized by beta-TrCP E3 ubiquitin ligase leading to ubiquitination and proteasomal degradation, keeping cytoplasmic levels low. Wnt signaling displaces complex via Dishevelled and GBP inhibiting GSK-3, preventing phosphorylation. Thus GSK-3 normally functions by degrading beta-catenin ventrally. Dorsal Wnt11 signaling inhibits GSK-3 allowing beta-catenin accumulation, nuclear translocation

Ref: NCBI Bookshelf, Molecular Biology of the Cell, Chapter 19: GSK-3 function - beta-catenin degradation in Wnt pathway.

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Cell Cycle Regulation

Which kinase is involved in regulating the initiation of DNA replication in S phase?

Initiation of DNA replication at licensed origins depends on two kinase families that separate licensing from firing. DDK kinase complex Dbf4-Cdc7 phosphorylates MCM2-7 helicase at N-terminal serine-threonine clusters, promoting Cdc45 recruitment. Second trigger is S-phase CDK activity supplied by cyclin E-CDK2 that peaks at G1/S border and cyclin A-CDK2 that sustains activity into S phase. Cyclin E-CDK2 phosphorylates Treslin/TICRR at threonine 969, MTBP, RecQL4, and orthologs of yeast Sld2 and Sld3, enabling their binding to BRCT repeats of TopBP1 and assembly of Cdc45-MCM-GINS active helica

Ref: Labib, Genes & Dev 2010, Origin Activation. Limas & Cook, Genes & Dev 2019, CDK Roles S Phase.

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Cell Cycle Regulation

Which kinase activates APC/C-Cdc20 to trigger the metaphase-anaphase transition?

Assembly and activation of APC/C-Cdc20 must occur only after CDK1 has driven mitotic entry, ensuring anaphase does not initiate prematurely. During G2, APC/C exists in unphosphorylated inactive conformation with weak affinity for Cdc20, while Cdc20 itself is kept inactive by CDK inhibitory phosphorylation and binding to checkpoint protein Mad2. Upon entry into mitosis, cyclin B-CDK1, the master mitotic kinase, phosphorylates multiple subunits including APC1 at loop region, APC3, and APC6, inducing conformational rearrangement exposing C-box binding groove. Polo-like kinase Plk1 adds further ph

Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 20: Mitotic Activation of APC/C.

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Cell Cycle Regulation

Which kinase plays a crucial role in chromosome condensation?

Transformation of extended interphase chromatin into compact rod-shaped mitotic chromosomes requires condensin complexes and coordinated kinase activation. Condensin II pentamer containing SMC2, SMC4 and subunits CAP-D3, CAP-G2, CAP-H2 resides in nucleus during interphase and initiates early looping as cells enter prophase. Condensin I pentamer with CAP-D2, CAP-G, CAP-H gains access to chromosomes after nuclear envelope breakdown in prometaphase. Activation depends on mitotic kinases: CDK1-Cyclin B phosphorylates CAP-D3 Threonines and CAP-H promoting ATPase activity, Polo-like kinase 1 phospho

Ref: Hirano, Condensin Complexes Drive Chromosome Condensation, Annu Rev Cell Dev Biol 2005; Alberts et al., Chapter 17, Condensins.

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Cell Cycle Regulation

Which kinase initiates DNA replication by phosphorylating helicase activators?

Authentic initiation of DNA synthesis requires coordinated activation of MCM2-7 helicase loaded at licensed origins. Two S-phase kinases perform this: Cdc7-Dbf4 complex called DDK phosphorylates N-terminal tails of MCM2, MCM4 and MCM6 promoting Cdc45 recruitment, while CDK2-Cyclin E and CDK2-Cyclin A phosphorylate Treslin, Ticrr, RecQL4 and TopBP1 creating phospho-binding sites for assembling replication machinery including Cdc45-MCM-GINS active helicase and Pol epsilon recruitment. Entry dataset incorrectly lists p53 as initiating kinase; biologically p53 acts opposite as genome guardian. Upo

Ref: Labib, Mechanism of DNA Replication Initiation by DDK and CDK, Science 2010; NCBI Bookshelf, Regulation of Origin Firing by CDK2.

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Cell Cycle Regulation

Which kinase phosphorylates the linker proteins between centrioles to allow centrosome separation?

Centriole pair remains linked throughout interphase by fibrous proteinaceous linker extending between proximal ends. Core constituents include large coiled-coil protein C-Nap1 anchored to centriole, rootletin forming 60 nm striated fibers, Cep68 and LRRC45 bridging. Dissolution in late G2 permits centrosome movement mediated by Eg5. Nek2A kinase, NIMA-related serine-threonine kinase, executes linker disassembly. Expression rises in S/G2, activity restrained in G1 by PP1 phosphatase binding and association with HEF1, MST2 and Hippo pathway components. Upon activation, Nek2 phosphorylates C-Nap1

Ref: Fry et al., Nek2 Kinase and Centrosome Linker Disassembly, Biochem J 2012; NCBI, Centrosome Separation Controls.

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Cell Cycle Regulation

What is the primary role of the Mps1 kinase?

Spindle assembly checkpoint activation hinges on kinase Mps1, also known as TTK, a dual specificity protein kinase recruited to unattached kinetochores. In prometaphase, Mps1 binds Ndc80 complex through competition with microtubules, positioning it near scaffold KNL1. Mps1 phosphorylates multiple MELT repeats on KNL1 at conserved methionine-glutamate-leucine-threonine motifs, converting them into phospho-docking sites for Bub3-Bub1 and Bub3-BubR1 complexes. Additionally, Mps1 phosphorylates Mad1 at C-terminus facilitating catalytic conversion of open O-Mad2 to closed C-Mad2, the conformer capa

Ref: London & Biggins, Mps1 Dependent KNL1 MELT Phosphorylation, Genes Dev 2014; Alberts et al., Chapter 17, SAC Kinase Cascade.

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Cell Cycle Regulation

Which of the following is NOT a function of CDK1-Cyclin B?

CDK1-Cyclin B, historically termed Maturation Promoting Factor, orchestrates early mitotic transformations upon nuclear translocation. Its catalytic subunit CDK1 becomes competent after binding Cyclin B, phosphorylation at Thr161 by CAK and dephosphorylation of inhibitory Thr14/Tyr15 by Cdc25C. Once active, it phosphorylates serine-threonine-proline motifs on diverse substrates: lamins A-C at Ser22, Ser392 causing depolymerization of intermediate filament network and nuclear envelope breakdown, condensin subunits Cap-D2, Cap-H2 stimulating chromosome condensation, Golgi matrix proteins GRASP65

Ref: Morgan, The Cell Cycle: Principles of Control, Chapter 3, Mitotic CDK Functions; Nature Reviews, Mitotic Entry and Mitosis.

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Cell Cycle Regulation

The primary function of Chk2 in DNA damage response is to:

Double-strand breaks caused by ionizing radiation or replication collapse activate upstream kinase ATM, recruited and stimulated by MRN complex bound to broken ends. Active ATM phosphorylates histone variant H2AX at Ser139 forming gamma-H2AX domains that recruit mediator proteins Mdc1, 53BP1 and effector kinase Chk2 through its FHA domain. ATM phosphorylates Chk2 at Thr68 within N-terminal SQ/TQ cluster, promoting dimerization via FHA domain exchange and autophosphorylation at Thr383/Thr387 in activation loop, yielding fully active kinase. Chk2 phosphorylates numerous downstream substrates, mo

Ref: Bartek et al., Chk2 Kinase and p53 After DNA Damage, Nat Rev Mol Cell Biol 2001; NCBI Bookshelf, ATM-Chk2-p53 Signaling.

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Cell Cycle Regulation

Which kinase phosphorylates Chk1 in response to replication stress?

Replication stress exposes extended single-stranded DNA regions coated by replication protein A, forming a key signaling platform. ATR kinase, recruited via ATRIP-interacting domain to RPA-ssDNA, is the principal sensor of this structure. At stalled forks, factors TopBP1, Claspin, Timeless-Tipin and Rad9-Rad1-Hus1 clamp augment ATR activation through direct binding and allosteric stimulation. Once activated, ATR directly phosphorylates checkpoint kinase Chk1 on serine residues 317 and 345 within its C-terminal regulatory domain. This modification relieves autoinhibition, enabling Chk1 catalyti

Ref: Cimprich & Cortez, ATR role in replication checkpoint, Nat Rev Mol Cell Biol 2008; NCBI Bookshelf, Replication Stress Response.

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Cell Cycle Regulation

Which kinase phosphorylates Knl1 to recruit checkpoint proteins at unattached kinetochores?

Assembly of spindle assembly checkpoint proteins at kinetochores requires phosphorylation-dependent creation of docking sites on outer kinetochore scaffold. KNL1, also called Blinkin or Spc105, contains multiple MELT repeats (Met-Glu-Leu-Thr) that become phosphorylated when kinetochore is unattached. The kinase responsible is monopolar spindle 1, abbreviated Mps1, conserved from yeast to humans, dual-specificity kinase that localizes to unattached kinetochores via its TPR domain interacting with Ndc80 complex and calponin homology domains. Mps1 phosphorylation of MELT motifs generates binding

Ref: London & Biggins, Genes Dev 2014, Mps1 and KNL1 Phosphorylation; Vleugel et al., J Cell Biol 2015, MELT Repeats.

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Cell Cycle Regulation

Which kinase is activated in response to double-strand DNA breaks?

DNA double-strand breaks are among most deleterious lesions, potentially generating chromosomal translocations if unrepaired. Detection relies on sensor complex MRN composed of Mre11, Rad50, and Nbs1 that binds broken ends and recruits serine/threonine kinase ATM, ataxia telangiectasia mutated, member of PI3K-like kinase family. ATM exists as inactive dimer; upon recruitment and interaction with Nbs1 C-terminus, it autophosphorylates at serine 1981, dissociates into active monomers, and phosphorylates hundreds of targets including histone variant H2AX at serine 139 forming gamma-H2AX foci that

Ref: Abraham, Genes Dev 2001, ATM and ATR Kinases; Shiloh & Ziv, Nature Rev Mol Cell Biol 2013, ATM Signaling.

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