Dec 13, 2019 · Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates.

Dec 13, 2019 · Understanding how p27 mediates cyclin-dependent kinase 4 (CDK4) assembly, activity, and sensitivity to the kinase inhibitor palbociclib. p27 binds CDK4 together with cyclin D (CycD), helping CDK4 to mature from the Hsp90 chaperone complex …

This study also suggests that phospho-p27 status serves as a surrogate marker for cdk4 activity, and may serve as a biomarker for patients to determine responsiveness to cdk4/6 inhibition.

Arguing for a two-state mechanism, we show that p27 bound to cyclin D-cdk4 can be both inhibitory and noninhibitory, due to its differential-growth-state-dependent tyrosine phosphorylation.

In quiescent NIH 3T3 cells expressing either ectopic cyclin D1 or activated MEK1, cyclin D1 is able to efficiently associate with CDK4; however, the complex is inactive. A significant percentage of the cyclin D1-CDK4 complexes are associated with p27 in serum-starved activated MEK1 or cyclin D1 cell lines.

D-type cyclin–Cdks are activated by mitogens to cause G0 exit and G1 progression. p27 has a dual role in the regulation of cyclin D–CDK4 and cyclin D–CDK6 complexes. Under adverse conditions,...

The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity.

Jun 21, 2022 · For Cdk4, p27 Y89 phosphorylation promotes activation of Cdk4 by CAK , and Y74 phosphorylation destabilizes the interaction between p27 and CyclinD/Cdk4, allowing Cdk4 to become active and initiate cell-cycle entry.

Jul 15, 1994 · Using a yeast interaction screen to search for proteins that interact with cyclin D1-Cdk4, we identified a 27 kDa mouse protein related to the p21 cyclin-Cdk inhibitor. p27 interacts strongly with D-type cyclins and Cdk4 in vitro and more weakly with cyclin E and Cdk2.

Feb 5, 2020 · Major Finding: Structural and biochemical studies revealed how p27 interacts with and activates CDK4. Concept: p27 binding prevented inhibition of CDK4 by palbociclib, a CDK4/6 inhibitor used in the clinic. Impact: Palbociclib may not work as previously envisioned, and p27′s role in CDK4 regulation is complex.